Implant with high vapor pressure medium

ABSTRACT

An implant delivery system can be configured to deliver an inflatable implant into a bladder via a urethra. The delivery system can comprise an elongate tubular body, an inflation tube and an implant decoupler. The tubular body can comprise a central lumen configured to hold an inflatable implant in an initial un-inflated state for delivery of the implant into the bladder. A method of use can include passing a distal tip of the elongate tubular body into the bladder. The implant can be inflated and released into the bladder.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.14/088,904 (Dkt. No. SOLACE.017C3), filed Nov. 25, 2013, which is acontinuation of U.S. patent application Ser. No. 13/925,659 (Dkt. No.SOLACE.017C1), filed Jun. 24, 2013, now U.S. Pat. No. 8,721,520, whichis a continuation of U.S. patent application Ser. No. 12/625,508 (Dkt.No. SOLACE.017A), filed Nov. 24, 2009, now U.S. Pat. No. 8,574,146,which claims priority to U.S. Provisional Patent Appl. Nos. 61/200,147(Dkt. No. SOLACE.017PR), filed Nov. 25, 2008, and 61/211,515 (Dkt. No.SOLACE.018PR), filed Mar. 31, 2009. The disclosures of theaforementioned applications are hereby incorporated in their entiretyherein by reference. Any and all priority claims identified in theApplication Data Sheet, or any correction thereto, are herebyincorporated by reference under 37 CFR 1.57.

This application is also related to U.S. patent application Ser. No.12/343,120 filed Dec. 23, 2008, now U.S. Pat. No. 8,298,132; U.S. patentapplication Ser. No. 10/391,448 filed Mar. 17, 2003, now U.S. Pat. No.7,470,228; U.S. patent application Ser. No. 10/391,446, filed Mar. 17,2003, now U.S. Pat. No. 6,976,950; U.S. Provisional Patent Appl. No.60/415,949, filed Oct. 3, 2002; U.S. patent application Ser. No.09/723,309, filed on Nov. 27, 2000, now U.S. Pat. No. 6,682,473; andU.S. Provisional Patent Appl. No. 60/197,095, filed Apr. 14, 2000. Thedisclosures of the aforementioned applications are hereby incorporatedin their entirety herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates generally to medical devices and methodsand apparatus related thereto for use within the body. The medicaldevices can include pressurized therapeutic devices, implants, implantdelivery devices, implant retrieval devices, expandable membraneenclosures or balloons, sponges, attenuators, space occupying members,space creating devices, drug delivery devices, data collection devices,nerve stimulation devices, wave producing devices, vibration producingdevices, pressure sensing devices, chemical sensing devices, volumesensing devices, and therapeutic devices. The medical devices can beused for many different purposes and in many places within the bodyincluding, but not limited to the following systems of the human body:cardiovascular, pulmonary, renal/urological, gastrointestinal,hepatic/biliary, gynecological, neurological, musculoskeletal,otorhinolaryngical and ophthalmic, as well as in and around organs ofthe body and in intra- and inter-organ space.

In some embodiments, methods and devices for maintenance of inflatedimplants within the body over time is discussed. In some embodiments,methods and devices for space creation or expansion within the body isdiscussed. In some embodiments, the treatment of disorders orpathological symptoms of the urinary tract caused by sudden fluctuationsof intravesical pressure is discussed.

An example of a problem where there is a need for improved medicaldevices and methods is dealing with pressure events in the body.Pressure changes are known to propagate through incompressible orcompressible fluids in various organs of the body. These pressure eventsor changes may be caused by a number of events including events withinthe body, such as a beating heart, breathing in the lungs, peristalsisactions in the GI tract, movement of the muscles of the body, or eventssuch as coughing, laughing, external trauma to the body, and movement ofthe body relative to gravity. As the elasticity, or compliance, of thesurrounding tissues and organs decreases, the propagation, magnitude, oramplitude of these pressure changes, waves, or events increases. Thesepressure events have many undesirable effects ranging from discomfort,to stress on the organs and tissue, to fluid leakage such as urinaryincontinence, to renal failure, stroke, atherosclerosis, heart attackand blindness.

SUMMARY OF THE INVENTION

Embodiments of the medical devices, apparatus and methods describedherein seek to overcome various problems in the medical field, includingthose described above. From this disclosure it will be appreciated thatalthough certain examples are provided, the methods and devices hereincan be used to provide similar or different treatments at the same orother sites within or in pressure communication with the body.

Certain embodiments comprise a method of treating a condition affectingthe bladder. The method can include the steps of implanting a deviceinto a human or animal body. The condition affecting the bladder cancomprise: urinary incontinence, urinary tract cancer, an infectionaffecting the bladder, or an inflammatory, condition affecting thebladder.

Different embodiments of delivery systems can be configured to deliveran implant into a bladder. Some delivery systems can comprise a guidebody, an implant advancer at least partially within the guide body and asyringe. The guide body can comprise a transurethral body sized to guidethe delivery system through a urethra and a depth stop surface at aproximal end of the transurethral body. The syringe can have a conduitwith a distal end of the conduit configured to couple to an implant,wherein at least a portion of the conduit is within the implantadvancer. The implant advancer and the syringe can be configured toslide relative to the guide body after the transurethral body has beeninserted into the urethra to thereby deliver an implant into thebladder. In some embodiments, the transurethral body has a lateralopening operable to deliver said implant away from a trigone region.

An implant delivery system can be configured to deliver an inflatableimplant into a bladder via a urethra. The delivery system can comprisean elongate tubular body, an inflation tube and an implant decoupler.The tubular body can comprise a central lumen configured to hold aninflatable implant in an initial un-inflated state for delivery of theimplant into the bladder. A method of use can include passing a distaltip of the elongate tubular body into the bladder. The implant can beinflated and released into the bladder.

A method of delivering an implant within a bladder according to certainembodiments can include the following steps. Inserting a transurethralbody into a urethra. The transurethral body can be part of an implantdelivery system having a guide body having the transurethral body and ameatal stop and an advancer. Placing the meatal stop against a meatus.Inserting a distal tip of the transurethral body within a bladder.Injecting liquid PFC into said implant. Moving an implant into thebladder with the advancer. Inflating an implant with air. Releasing theimplant from the delivery system. Removing the delivery system from thebladder.

Some methods can further comprise additional steps such as: identifyinga back wall of the bladder, wherein releasing the implant furthercomprises releasing the implant in a direction away from the trigonalarea, wherein injecting further comprises injecting the liquid PFC intothe implant prior to the step of moving the implant into the bladder,and wherein injecting further comprises injecting the liquid PFC intothe implant prior to releasing the implant from the delivery system.

An additional method of delivering an implant within a bladder cancomprise the steps of: inserting a cannulated delivery device within aurethra; passing a distal tip of said delivery device beyond a bladdersphincter into the bladder; causing or allowing an implant to expand outof a lateral aspect of said delivery device wherein said expansionoccurs in a direction substantially opposite to that of a trigone regionof the bladder and wherein said expansion is operable to open a flap oraperture of said aspect; disengaging said implant from said removaldevice; and removing said delivery device.

According to some embodiments, an implant delivery system can beconfigured to deliver an inflatable implant into a bladder via aurethra. The delivery system can comprise an elongate tubular body, aninflation tube and an implant decoupler. The elongate tubular body canbe sized to pass through a urethra into a bladder. The tubular body cancomprise a central lumen configured to hold an inflatable implant in aninitial un-inflated state for delivery of the implant into the bladderand a lateral opening operable to deliver the inflatable implant fromthe central lumen into the bladder away from a wall of the bladder. Theinflation tube can be positioned within the central lumen of the tubularbody, the inflation tube configured to couple with the inflatableimplant to allow inflation of the inflatable implant from within thetubular body. The implant decoupler can be positioned within the centrallumen of the tubular body around the inflation tube. The implantdecoupler can be configured to decouple the inflatable implant from theinflation tube after inflation of the inflatable implant from theun-inflated state to an inflated state.

In some embodiments, a method of delivering an inflatable implant into abladder via a urethra can include one or more steps. The one or moresteps can include the at least one of the following. Inserting anelongate tubular body of a delivery device within a urethra, theelongate tubular body comprising a central lumen holding an inflatableimplant in an initial un-inflated state for delivery of the implant intoa bladder. Passing a distal tip of the elongate tubular body into thebladder. Inflating the implant and thereby advancing the implant fromwithin the central lumen to outside of the central lumen and into thebladder. Disengaging the inflatable implant within the bladder from saiddelivery device. Removing the delivery device from the bladder.

According to some embodiments, the method may include one or more of thefollowing additional steps. Inflating the implant can further compriseexpanding the implant out of a lateral opening of the elongate tubularbody. Expanding can further comprise expanding the implant out of thelateral opening in a direction substantially opposite to that of atrigone of the bladder. Expanding can further comprise expanding theimplant out of the lateral opening in a direction towards a dome of thebladder.

Further features and advantages of the present invention will becomeapparent to those of skill in the art in view of the detaileddescription of preferred embodiments which follows, when consideredtogether with the attached drawings and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to better understand the disclosure and to see how it may becarried out in practice, some preferred embodiments are next described,by way of non-limiting examples only, with reference to the accompanyingdrawings, in which like reference numerals denote corresponding thoughnot necessarily identical features consistently throughout theembodiments in the attached drawings.

FIG. 1 illustrates maximum urethral pressure against intravesicalpressure during normal voiding.

FIG. 2 illustrates the intravesical pressure exceeding the maximumurethral pressure in a noncompliant bladder.

FIG. 3 illustrates an intravesical pressure spike exceeding the maximumurethral pressure during stress incontinence.

FIG. 4A illustrates the relationship between intravesical pressure anddetrusor pressure during cough-induced urgency or frequency.

FIG. 4B illustrates the relationship between intravesical pressure anddetrusor pressure during non-cough-induced urgency or frequency.

FIG. 5 is a schematic top plan view of an implant.

FIG. 5A is a side elevational view of FIG. 5.

FIGS. 5B-G show various types and shapes of implants.

FIGS. 5H-I show a top and cross-sectional view of an implant.

FIGS. 5J-K show a top and cross-sectional view of an implant.

FIG. 5L shows a toroidal implant within the bladder when the bladder isfull.

FIGS. 5M-N show a toroidal implant within the bladder when the bladderis empty.

FIG. 6 is a side elevational schematic view of a delivery system fordeploying an implant.

FIG. 6A is a side elevational schematic view of another delivery system.

FIG. 6B is a cross-section through the line 6B-6B in FIG. 6.

FIG. 7A is an elevated side view of one embodiment of a delivery system.

FIG. 7B is an elevated side view of the delivery system of FIG. 7B withthe implant ejected.

FIG. 8A is a detail schematic view of the filling tube of a deliverysystem engaged within the valve of an implant.

FIG. 8B is a detail schematic view as in FIG. 7A, with the filling tubeproximally retracted from the valve.

FIG. 9 is a side view of another embodiment of a delivery system.

FIG. 9A is a side view of the delivery system of FIG. 9 showingseparable components thereof.

FIGS. 10A-E show different embodiments of a tip or end portion of atransurethral body for a delivery system.

FIGS. 11A-C show an additional embodiment of a tip or end portion of atransurethral body for a delivery system with a dumbbell shaped implant.

FIG. 12A is a side view of an embodiment of a delivery system with anangularly offset syringe.

FIG. 12B is a side view of an embodiment of a delivery system with anangularly offset syringe and transurethral body.

FIG. 12C is a side view of part of an embodiment of a delivery systemwith a syringe having a flexible conduit and a rigid tip.

FIG. 13 is a schematic representation of a delivery system needle orconduit tip within a valve of an inflatable implant.

FIGS. 13A-E show different embodiments of different shaped needle orconduit cross-sections taken along line A-A of FIG. 13.

FIGS. 14A-C are side views of different embodiments of transurethralbodies of a delivery system.

FIGS. 15A and B are representations of the shape of the bladder withdifferent levels of fluid and relating to part of a delivery method.

FIGS. 16A and B show certain method steps for preparing a deliverysystem to deliver an implant.

FIGS. 17A-D are side views of different embodiments of transurethralbodies of a delivery system within the bladder and urethra.

FIGS. 18A-D show method steps for inserting an implant according to oneembodiment.

FIG. 18E illustrates a method step of inflating an implant.

FIGS. 18F-H illustrate methods of releasing an implant from a deliverysystem.

FIGS. 19A-E show methods of removing an implant from the bladder.

FIGS. 20A-C relate to methods of locating an implant for retrieval,where A uses an optical instrument, B uses suction and in C the implantis tethered to a body structure.

FIG. 21 is an embodiment of a retrieval instrument engaging an implant.

FIG. 22A is an embodiment of a retrieval instrument engaging an implanthaving independently movable sets of prongs.

FIG. 22B is an embodiment of an implant retrieval instrument with avacuum engaging an implant.

FIGS. 23A-H illustrate different shapes and configurations of implantsdesigned to enhance retrieval.

FIG. 24 is a side elevational view of a removal system.

FIG. 25A shows a removal system with an optical instrument, a cannula,and a grasper engaging an implant.

FIG. 25B has the removal system of FIG. 25A where a piercing element iscutting the implant.

FIG. 25C is a view of the pierced implant being pulled into the cannulaby the grasper.

FIG. 25D shows the implant removed from the bladder into the cannula.

FIGS. 26A-B are views of a removal system having a cage, basket or netfor removing an implant from the body.

FIG. 26C shows another embodiment of a cage, basket, or net removalsystem.

FIGS. 27A-B illustrate embodiments of a removal system that uses heat todeflate a balloon-like implant.

FIG. 28A is a side view of a cannula having a thin film resistor on theend.

FIG. 28B is an end view of the cannula of FIG. 28A.

FIG. 29A is a schematic side view of a removal system that uses heat onthe cannula to deflate a balloon-like implant.

FIG. 29B is a schematic detail view of the removal system of FIG. 29A.

FIG. 29C is an embodiment of a removal system similar to that shown inFIG. 29A.

FIGS. 30A-D present graphs of attenuation/pressure reduction vs. timefor various attenuation device air volumes.

FIGS. 31A-D show pressure vs. time curves generated by a bench topbladder simulator.

FIG. 32A illustrates a bladder experiencing pressure which causes urineleakage.

FIG. 32B shows the bladder of FIG. 32A with an implant that absorbs thepressure so that there is no urine leakage.

FIG. 33 is a chart of the gas and fluid volumes over time of arecharging implant.

FIG. 34A shows a side view of a corrugated implant with ridges in anunexpanded position.

FIG. 34B shows the cross-section of the implant from FIG. 34A in theexpanded position.

FIGS. 35A and B depict an implant with a frame including an “x” lattice.

FIGS. 35C and D illustrate implants at least partially enclosed in aninelastic net.

FIG. 36 charts the pressure within an implant verses the volume of theimplant.

FIGS. 37A and B are detail views of implant membranes with curvilinearelements or interlocking elements that limit expansion along one or moreaxis.

FIGS. 38A and B show cross-sectional side views of an implant within abreast.

FIG. 39 is a side view of two vertebral bodies where one implantsurrounds and connects the vertebral bodies and one implant is connectedto opposing spinous processes.

FIG. 40 shows a prepackaged implant in a liquid bath.

FIGS. 41A-C show cross-sectional axial views of implants within a skulland under the scalp.

FIGS. 42A-B show a long bone with implants for compressing or tensioningthe bone.

FIG. 43 is cross-sectional view of a vertebral body and disc in whichexpandable implants have been implanted.

FIG. 44 is a perspective view of a brace for a movable joint, such asthe elbow or knee.

FIG. 45 is a sagittal view of a foot with various implants.

FIG. 46 shows a simplified diagram of the digestive system and variousimplants.

FIGS. 47A-F show various tissue and bone anchor embodiments havinginflatable membrane enclosures.

FIGS. 48A and B show cross-sectional views of a penis and penileimplants.

FIGS. 49A and B show cross-sectional view of a kidney and an uretalstent device.

FIGS. 50A and B show a simplified diagram of a heart and relatedvasculature with various implants at various sites.

FIGS. 51A-C show different implants used as drug delivery devices.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Medical devices, methods, and apparatus related thereto for use withinthe body are disclosed. The medical devices can include pressurizedtherapeutic devices, implants, implant delivery devices, implantretrieval devices, expandable membrane enclosures or balloons, sponges,attenuators, space occupying members, space creating devices, drugdelivery devices, data collection devices, nerve stimulation devices,wave producing devices, vibration producing devices, pressure sensingdevices, chemical sensing devices, volume sensing devices, andtherapeutic devices. The medical devices can be used for many purposesand in many places within the body including, but not limited to thefollowing systems of the human body: cardiovascular, pulmonary,renal/urological, gastrointestinal, hepatic/biliary, gynecological,neurological, musculoskeletal, otorhinolaryngical and ophthalmic, aswell as in and around organs of the body and in intra- and inter-organspace.

In one particular aspect, the disclosure relates generally to the fieldof urology and gynecology, and in particular to the treatment ofdisorders of the urinary tract caused by sudden fluctuations ofintravesical pressure. More specifically, in this aspect methods anddevices are provided for the diagnosis and treatment of urinarydisorders such as incontinence, urgency, frequency, interstitialcystitis, irritable bladder syndrome and neurogenic bladders.

Various embodiments of pressurized therapeutic devices that maintain agiven pressure and or volume over time despite gaseous exchange areprovided, other embodiments inflate or deflate over a given time periodand further embodiments provide a constant force against, within orbetween a tissue, vessel, organ, or body cavity. Certain embodiments aredesigned to maintain inflation in oxygen depleted environments.

Various instruments and implants are provided herein for theimplantation of medical devices within the bladder via the urethra, opensurgery or percutaneously through the abdomen, back, vagina, bowel,rectum, or perineum. Certain embodiments of the implantable medicaldevice may comprise one or more expandable membrane enclosure orballoon, sponge, attenuator, space occupying member, drug deliverydevice, data collection device, nerve stimulation device, wave producingdevice, vibration producing device, pressure sensing device, chemicalsensing device, volume sensing device, or a therapeutic device. Fromthis disclosure it will be appreciated that although the examplesprovided deal primarily with intravesical applications the methods anddevices herein can be used to provide treatment at sites adjacent thebladder or between layers of bladder tissue. Further, the devices andmethods herein may be used or applied within or proximal to other organsand sites in the body such as the heart, lung, cranium, cardiovascularsystem, breasts, abdominal area or cavity, eye, testicles, intestines,stomach, or other organs or tissues.

Some embodiments are directed to methods and apparatus for measuringand/or attenuating and/or baffling transient pressure waves inrelatively incompressible materials in organs of the body. Illustrativeembodiments discussed below relate generally to the fields of urologyand gynecology, and in particular to the treatment of disorders of theurinary tract exacerbated by sudden fluctuations in intravesicalpressure. However, as will be readily understood by those skilled in theart, and as described below, the devices and methods are not limited tothe fields of urology and gynecology and methods and apparatuses ofembodiments disclosed herein may be used in other organs of the body aswell to attenuate and/or baffle pressure transients or reversibly occupyintraorgan or interorgan space.

Certain embodiments dampen transient intravesical pressure includingpressure spikes experienced by the urinary tract. During a transientpressure event, the bladder becomes a relatively non-compliantenvironment due to a number of factors including the pelvic skeletalstructure, the compressive loads of contracting tissues bounding thebladder or the decreased compliance of the musculature, incompressiblebehavior of urine, nerve or connective tissue of the bladder. Factorscontributing to the reduced compliance of the bladder are aging,anatomic abnormalities or trauma to the structures of the pelvis andabdomen.

Urine is primarily composed of water and is virtually incompressible inthe typical pressure ranges present within the human bladder. Therelationship between the maximum urethral pressure and the intravesicalpressure for normal voiding of the bladder is well defined. Withreference to FIG. 1, relaxation of the urethra occurs before thedetrusor muscle contracts to cause the intravesical pressure 320 toexceed the urethral pressure 322 during normal voiding. As would beobvious to one skilled in the art, the pressures discussed herein aregauge or relative pressures except where absolute pressures and/oratmospheric pressures are specifically mentioned.

The bladder serves two mechanical functions: 1) low-pressure storage and2) high-pressure voiding. During the storage or filling phase, thebladder receives urine from the kidneys. Compliance of the bladder isdefined as the ratio of the change in volume to the change in pressure,and the static compliance of the bladder is measured during a typicalurodynamic evaluation. The static compliance index is measured byfilling the bladder to cystometric capacity and allowing the pressuresto equilibrate for a time period of approximately sixty seconds. Thestatic compliance index is calculated by dividing the bladder capacityby the detrusor pressure at the end of filling. A normal bladder willtypically exhibit static compliance between 15 and 30 ml/cm H₂O. A lowstatic compliance bladder typically will have a compliance index of lessthan 10 ml/cm H₂O. With reference to FIG. 2 which illustrates differentpressures for a non-compliant bladder, a low static compliance bladdertypically is poorly distensible and has a high end-filling pressure. Theintravesical pressure 320 increases to higher levels to exceed themaximum urethral pressure 324. The steady state or static compliance ofthe bladder is used to diagnose patients with neuropathic problems suchas damage to the lower motor neurons, upper motor neurons, or multiplesclerosis. In addition, the steady state compliance of the bladder isalso used, in some cases, to attempt to diagnose problem ofincontinence, including urgency, frequency and cystitis.

In general, intravesical pressure spikes result from volumetric tissuedisplacement in response to gravity, muscular activity or rapidacceleration. The lack of compliance of the bladder and the urinecontained in the bladder with respect to events of high frequency,result in minimal fluidic pressure attenuation of the higher frequencypressure wave(s) and results in high intravesical pressures that aredirectly transmitted to the bladder neck and urethra, which may or maynot cause detrusor contractions. Under these conditions, the urethra mayact as a volumetric pressure relief mechanism allowing a proportionalvolume of fluid to escape the bladder, to lower the intravesicalpressure to a tolerable level. The urethra has a maximum urethralpressure value, and when the intravesical pressure exceeds the maximumurethral pressure, fluid will escape the bladder. Under theseconditions, nerve receptors in the bladder and/or bladder neck and/ortrigone trigger a detrusor contraction that may lead to micturition(frequency) or may subside without micturition (urgency) or may lead tothe intravesical pressure exceeding the maximum urethral pressureresulting in fluid escaping the bladder (incontinence). Under theseconditions, waves hitting and/or expanding the bladder wall, may cause apatient with cystitis to exhibit significant pain.

Incontinence is common in males who have undergone radicalprostatectomy, particularly where the sphincter has been compromised. Inthese patients, attenuation in the bladder reduces the intravesical peakpressures, resulting in less urine leakage. The attenuation requirementsin these patients can include short duration pressure changes—such as,for example, 50 to 400 ms—and long duration pressure changes—such as,for example, greater than 500 ms—depending on the magnitude of damage tothe urinary sphincter.

The inventors of the present application have recognized that for thevast majority of patients suffering from problems of urinary tractdisorders such as frequency, urgency, stress and urge incontinence andcystitis, the cause and/or contributor to the bladder dysfunction is areduction of overall dynamic bladder compliance rather than steady statebladder compliance. These patients may often have bladders that arecompliant in steady state conditions, but have become non dynamicallycompliant when subjected to external pressure events having a shortduration of, for example, less than 5 seconds or in some cases less than2 seconds or even less than 0.01 seconds. Reduction in dynamiccompliance of the bladder is often caused by some of the same conditionsas reduction of steady state compliance including aging, use,distention, childbirth and trauma. The anatomical structure of thebladder in relation to the diaphragm, viscera, and uterus (for women)causes external pressure to be exerted on the bladder during talking,walking, laughing, sitting, moving, turning, and rolling over.

The relationship between intravesical pressure 320 and the maximumurethral pressure 324 for a patient suffering from stress incontinencedue to lack of dynamic compliance in the bladder is illustrated in FIG.3. When the patient coughs (or some other stress event occurs), a spike326 will occur in the intravesical pressure. Intravesical pressurespikes in excess of 120 cm H₂O have been urodynamically recorded duringcoughing, jumping, laughing or sneezing. When the intravesical pressureexceeds the maximum urethral pressure value, leakage occurs. In order toretain urine during an intravesical pressure spike, the urinaryretention resistance of the continent individual needs to exceed thepressure spike. Urinary retention resistance can be simplified as thesum total of the outflow resistance contributions of the urethra,bladder neck and meatus. In female patients, it is generally believedthat the largest resistance component is provided by the urethra. Onemeasure of urinary resistance is the urodynamic measurement of urethralleak pressure. The incontinent individual typically has a urethral leakpressure less than 80 cm H₂O. The decline of adequate urinary retentionresistance has been attributed to a number of factors including reducedblood flow in the pelvic area, decreased tissue elasticity, neurologicaldisorders, deterioration of urethral muscle tone and tissue trauma.

In practice, the urethral leak point pressure is determined by fillingthe bladder with a known amount of fluid and measuring the intravesicaland abdominal pressures when there is a visible leak from the urethrawhile the patient is “bearing-down” (valsalva). With an attenuationdevice in the bladder, the measured intravesical leak point pressuretypically increases due to the absorption of some the abdominal energyby the attenuation device. In this case, the patient has to push harderto achieve the same intravesical pressure. Since the abdominal musclesand muscles surrounding the urethra both contract simultaneously duringa valsalva maneuver, the measured intravesical leak point pressure andurethral resistance increases when the attenuation device is in thebladder.

Urinary disorders, such as urgency, frequency, otherwise known asoveractive bladder, and interstitial cystitis are caused or exacerbatedwhen rapid pressure increases or rapid volume increases or otherirritable conditions within the bladder cause motor neurons to sendsignals to the brain to begin the cascade of events necessary forurination. External pressure exerted on the bladder may result in adetrusor contraction that may result in urgency, frequency orincontinence. See FIGS. 4A (cough-induced urgency/frequency) and 4B(non-cough-induced urgency/frequency). With reference to FIG. 4A, acoughing event 328 induces increased intravesical pressure 320 whichresults in increased detrusor pressure 330. An increase in the detrusorpressure 330 generally is associated with increased urgency, frequency,or incontinence. Urinary disorders such as interstitial cystitis orirritable bladder conditions are a chronic inflammatory condition of thebladder wall, which includes symptoms of urgency and/or frequency inaddition to pain. Therefore, the problem of a pressure spike in thefunctionally noncompliant bladder can be further exacerbated by a nearlysimultaneous contraction of the bladder and a relaxation of the urethra.

Some embodiments provide methods and devices for treating and/orcompensating for reduced dynamic compliance of the bladder. In oneembodiment, a device having a compressible element is placed within thehuman urinary bladder, in a manner that allows the compressible elementto act as a pressure attenuator to attenuate transient pressure events.The term attenuator refers generally to devices that attenuate pressure,force, or energy by dissipating or dampening the pressure, force, orenergy. Gases, such as atmospheric air, carbon dioxide, nitrogen, andcertain perfluorocarbons (PFC) are very compressible in the pressureranges typically encountered in the human bladder, and may be used inattenuation devices inserted in the bladder. Furthermore, when comparedto the tissues encompassing urine, gases are significantly morecompliant than the immediate environment. The addition of a volume ofgas acts as a low rate spring in series with the native fluidic circuitof the urinary tract.

In accordance with one embodiment, an attenuation device is placedwithin the human urinary bladder. The attenuation device can be apressurized container. The container can take many forms including asphere. The attenuation device is intended to be untethered in thebladder and is intended to remain in the bladder for between severalhours and one year, between one week and six months, or between one dayand three months. The attenuation device is a small elastomeric gas cellwith a relaxed (unstretched) volume of between 1 and 500 cc, morepreferably between 10 and 180 cc and more preferably still, between 25and 60 cc. The attenuation device is a unitary component but can becomprised of two or more subcomponents. The attenuation device can bemade with or without a seam. The attenuation device has a substantiallyuniform wall thickness of between 0.25 inch to 0.0001 inch, morepreferably between 0.0005 inch and 0.005 inch, but could vary greatly,and still perform the intended function. In the embodiment describedabove, attenuation devices having gas cells that are free-floating inthe bladder have been described. In other embodiments, gas cells orsimilar attenuation devices could be surgically affixed to the bladderwall through the use of suture, staples and other accepted methods orplaced submucosally or intramuscularly within the bladder wall. Otherembodiments could also include attenuation devices with programmable,variable and adjustable buoyancy by using ballasting, specificinflation/deflation solutions, alternative materials of construction orby other means.

Referring to FIGS. 5 and 5A, one embodiment of attenuation device 66 isillustrated which comprises a moveable wall such as on an inflatablecontainer 68. The inflatable container 68 is illustrated as having agenerally circular profile, although other profiles may be utilized. Thediameter of the inflatable container 68 may be varied within the rangeof from about 0.25 inches to about 6 inches in an embodiment involvingthe implantation of only a single attenuation device. Many embodimentsof the inflatable containers 68 will have a diameter within the rangefrom about 1 inch to about 3 inches, with a total volume within theranges recited above. In general, the specific dimensions andconfiguration of the inflatable container 68 are selected to produce anattenuation device having a desired volume and a desired dynamiccompression range, and may be varied from spherical to relatively flatas will be apparent to those of skill in the art based upon thedisclosure herein. In certain embodiments, two or more discreetinflatable containers 68 are utilized. The sum of the volumes of themultiple containers will equal the desired uncompressed displacement.

The inflatable container 68 illustrated in FIGS. 5 and 5A comprises aflexible wall 70, for separating the contents of the attenuation device66 from the external environment. Flexible wall 70 comprises a firstcomponent 74 and second component 76 bonded together such as by a seam78. In the illustrated embodiment, the first component 74 and secondcomponent 76 are essentially identical, such that the seam 78 is formedon the outer periphery of the inflatable container 68. Seam 78 may beaccomplished in any of a variety of manners known in the medical devicebonding arts, such as heat bonding, adhesive bonding, solvent bonding,RF or laser welding, or others known in the art.

The flexible wall 70, formed by a bonded first component 74 and secondcomponent 76, defines an interior cavity 72. As is discussed elsewhereherein, interior cavity 72 preferably comprises a media that can includea compressible component, such as gas, or foam. Other media orstructures capable of reduction in volume through a mechanism other thanstrict compression may also be used. For example, a material capable ofundergoing a phase change from a first, higher volume phase to a second,lower volume phase under the temperature and pressure ranges experiencedin the bladder may also be used. In one embodiment, the media cancomprise a liquid that forms a solid or foam after implantation. In someembodiments the media comprises a solid.

In order to minimize trauma during delivery of the attenuation device66, the attenuation device is preferably expandable from a first,reduced cross-sectional configuration to a second, enlargedcross-sectional configuration. The attenuation device 66 may thus betransurethrally deployed into the bladder in its first configuration,and enlarged to its second configuration once positioned within thebladder to accomplish the pressure attenuation function. Preferably, acrossing profile or a greatest cross-sectional configuration of theattenuation device 66 when in the first configuration is no greater thanabout 24 French (8 mm), and, preferably, no greater than about 18 French(6 mm). This may be accomplished, for example, by rolling a deflatedinflatable container 68 about a longitudinal axis, while the interiorcavity 72 is evacuated. Once positioned within the bladder, the interiorcavity 72 is filled with the media to produce a functional attenuationdevice 66.

To facilitate filling the interior cavity 72 following placement of theattenuation device 66 within the bladder, the inflatable container 68 ispreferably provided with a valve 80. In the illustrated embodiment,valve 80 is positioned across the seam 78, and may be held in place bythe same bonding techniques utilized to form the seam 78. Valve 80 maybe omitted in an embodiment in which the attenuation device 66 isself-expandable.

Valve 80 generally comprises an aperture 82, for receiving a fillingtube therethrough. Aperture 82 is in fluid communication with theinterior cavity 72 by way of a flow path 83. At least one closure member84 is provided for permitting one way flow through flow path 83. In thismanner, a delivery system and filling device can be utilized to displaceclosure member 84 and introduce compressible media into the interiorcavity 72. Upon removal of the filling device, the closure member 84prevents or inhibits the escape of compressible media from the interiorcavity 72 through the flow path 83.

Thus, the closure member 84 is preferably movable between a firstorientation in which it obstructs effluent flow through the flow path 83and a second position in which it permits influent flow through the flowpath 83. Preferably, the closure member 84 is biased in the firstdirection. Thus, forward flow may be accomplished by either mechanicallymoving the closure member 84 into the second position such as using afilling tube, or by moving the closure member 84 into the secondposition by exerting a sufficient pressure on the compressible media inflow path 83 to overcome the closure bias. Any of a wide variety ofvalve designs may be utilized in the implant 66 as will be apparent tothose of skill in the art in view of the disclosure herein.

Various coatings may be used to enhance the biocompatibility of theimplantable devices and associated insertion or removal devicesdescribed herein. Lubricating coatings, substances, and substrates maybe used to facilitate insertion or removal. In one embodiment, thedevice incorporates biocompatible coatings or fillers to minimizeirritation to the bladder wall and mucosa and/or to inhibit theformation of mineral deposits (encrustation) or biofilm formation. Suchdevice treatments may also inhibit films, deposits or growths within oron the surface of the device. Materials can be coated onto the surfaceor incorporated within the wall of the device. Biocompatible lubricatingsubstances may be used to facilitate the placement of the attenuationdevice/fill tube within a lumen of an introducer.

FIGS. 5B-5G show various other types of implants. The implants shown canbe used as attenuation devices or for other therapeutic, aesthetic,and/or medicinal purposes as discussed herein. Shapes and types ofimplants can include a sphere, toroid, hemi-toroid, egg-shaped, sponge,snake, cylindrical coil, coiled, tethered, disc-like, rod, flat envelope(i.e., two sheets with a seam around the edge), chain of beads, etc.

In certain other embodiments the cross-section of the implant is noncircular such as oval, triangular, rectangular, or any other geometricshape. In another embodiment the cross-section is wavy, variable,irregular, repeating such as repeating series of linked spheres in fluidcommunication with each other. In yet another embodiment the implant isinitially provided in the form of a rod, either solid or partiallyinflatable, that forms a short but wide spiral, or spring like devicehaving one or more coils. This embodiment is particularly useful inenvironments wherein the transverse size or shape, e.g., diameter, ofthe treatment region is not certain or changes over time because thecoil will tend to expand or contract accordingly.

In some embodiments the implant is at least partially solid. Forexample, solid portions 81 can be added to an implant 66. The solidportions can serve many functions such as, structural support, drugdelivery, expansion or compression limiters, etc. In some embodiments,the solid portions 81 can comprise a drug delivery device, such as abuilt-up drug deposit. For example, FIGS. 5H and 5I show an implant 66Ain the shape of a toroid. The implant 66A can be an inflatable implantdefining an enclosure 85. The enclosure 85 can be flexible. In someembodiments, the enclosure 85 can assume a first deflated configurationand a second expanded and inflated configuration. The implant 66A can bean attenuation device. The implant 66A can have solid portions 81surrounding the device. As shown, the solid portions can be ribs on theenclosure 85 or ribs that at least partially surround the enclosure 85.

In some embodiments an implant can be configured to include one or morechambers or segments to serve specific functions. The chambers cancontain various substances and can be for various purposes such as, forcontaining combinations of gases, liquids, and/or therapeutic agents.

For example, FIGS. 5J and K show a toroid shaped implant 66B with twochambers 73, 79. In one embodiment one chamber 79 is filled with a drugand the other 73 is filled with an inflating media. The chambers 73, 79can be separated by a wall 75. One or both of the chambers can be usedas a drug delivery device. For example, chamber 79 can have holes 77 onthe outer surface of the implant 66B to allow a drug to diffuse throughthe chamber wall into the implant's 66B surroundings. The size anddensity of the holes 77 in the film can be used to control the rate ofdrug flow from the chamber 79 to the bladder or other bodily region. Insome embodiments, the outer surface or portions of the outer surface ofthe implant are permeable to certain substances such as, air or water.This can allow the substance to enter and leave the chamber. When thesubstance leaves the chamber it can take a drug or other chemical withit to the surroundings of the implant 66B.

Pressure on the inside of the implant 66 can also be used to control therate of drug diffusion. In another embodiment, material selection andthickness is used to control the rate of drug release. In otherembodiments, barrier layers and multilayered structures are used toobtain the desired diffusion rate. For example, the outside surface ofthe implant 66 can be configured to have barrier layers or bemultilayered. Barrier layer selection can be used in addition to, orwithout coatings to control the diffusion rates of chemicals and gaseswithin the implant. Finally, in certain other embodiments a spring andchamber, or piston can be used to create a near constant pressure on thedrug and control the rate of release.

The human urinary bladder is a solid, muscular, and distensible organthat sits on the pelvic floor. It collects urine excreted by the kidneysprior to disposal by urination. Urine enters the bladder 5 via theureters 11 and exits via the urethra 7 (FIG. 5L).

The walls of the bladder are mostly comprised of muscle tissue. Thismuscle tissue is known as the detrusor muscle, and is a layer of theurinary bladder wall made of smooth muscle fibers arranged in spiral,longitudinal, and circular bundles. When the bladder is stretched,nerves are activated which signals to the parasympathetic nervous systemto contract the detrusor muscle. This encourages the bladder to expelurine through the urethra. For the urine to exit the bladder, both theinternal sphincter and the external sphincter need to open. The urinarybladder can contain a wide range of urine volumes, from 0 to as much as600 ml of urine. Typically, in a female, bladder urine volumes in thebladder range from 0 to 300 ml. Typically, in a female, a full bladderwill contain 250 to 300 ml.

The neck of the bladder 13 is the area immediately surrounding theurethral opening; it is the lowest and most fixed part of the organ. Inthe male it is firmly attached to the base of the prostate, a gland thatencircles the urethra. The bladder neck 13 is commonly more or lessfunnel-like in shape. The angle of inclination of the sides of thisfunnel varies based on the degree to which the bladder is full, and alsovaries during filling and emptying of the bladder. A very full distendedbladder will have a bladder neck 13 with more oblique walls, and abladder that is emptying or empty will be more acute. The posteriorportion of the bladder neck 13 that is contiguous with the base of thebladder has a region containing a high density of sensory nerves. Thisregion is triangular in shape and is known as the trigone region 9. Thisinverted triangle defined by the urethra 7 (the vertex of the triangle)and the ureteral orifices 11 at each corner of the base of the triangle.The ureteral orifices are the locations where the ureters enter thebladder.

The highest concentration of sensory nerve receptors in the bladder canbe found in the trigone region 9. Anything that causes pressure,friction, or irritation on this region can cause a number ofmorbidities, including urgency, frequency, pain and/or irritation. Thebladder neck 13 contains stretch receptors, and anything that lodges inor otherwise stretches the bladder neck will likewise be veryuncomfortable. When designing a device that is to reside in whole or inpart in the bladder, the comfort of that device will be significantlyimpacted by the device's ability to minimize or avoid contact with thesetwo particularly sensitive areas.

In addition, the bladder does not contract or expand uniformly. Forexample, when the bladder is full it is quasi-spheroid or ovoid inshape. Its muscular walls are stretched out. During micturition, as thebladder empties, the superior and inferolateral walls contract.Wrinkles, or rugae, form in these walls as they shrink. The bladder neckand trigone area is more firmly anchored to underlying tissue and doesnot shrink as significantly or form rugae. Consequently the shrinkage ofthe bladder is not uniform and most of the reduction in size comes fromthe shrinkage of the superiolateral and inferolateral walls, and fromthe superior wall, or dome, becoming convex as it collapses towards thetrigone and bladder neck area

Accordingly, intravesical implants can preferably be configured toavoid, or not be capable of entering the bladder neck 13 and trigonearea 9. This can reduce or eliminate irritation to these sensitive areascontaining the majority of the pain receptors in the bladder. Also,recognizing the non-uniform contraction of the bladder as it empties,other embodiments can include devices that reside in the foldedperimeter of the bladder and/or comprise an open center (such as atoroid) or perforated center (i.e. a central region that permits flowthrough) that does not contact the sensitive trigone area, andoptionally can remain in a relatively fixed location.

If the implant gets too large, then it can occupy too much of the volumeof the bladder and diminish its capacity to the point where the patientwill need to urinate more frequently. Such a device will diminish the“functional capacity” of the bladder. Accordingly, one or moreembodiments of devices are adapted to not occupy more than 10% of atypical functional capacity which corresponds to 25 to 30 ml in women,and up to twice that amount in men. In other embodiments, the volume ofthe implant can be as high as 20%-50% of functional capacity or inextreme cases at or beyond functional capacity.

One or more implants provided herein may be suitable for providing aplatform for an intravesical device comprising a drug delivery device,data collection device, attenuation device, nerve stimulation device,wave producing device, vibration producing device, pressure sensingdevice, chemical sensing device, volume sensing device, pH sensing or atherapeutic device.

In one embodiment, an implant 66C is ring or toroid shaped, as shown inFIG. 5L. The implant 66C can be adapted within the bladder 5 such thatafter implantation it resides above the trigone region 9 and bladderneck 13 and is incapable of entering the trigone region 9 and bladderneck 13 when the bladder is full (FIG. 5L), empty (FIGS. 5M and N) or inthe process of being filled.

In one or more embodiments the outer diameter of a ring, toroid, orcoiled implant can be around 1 inch to 6 inches, and more preferably 2.5inches to 4.5 inches. The cross sectional diameter of the implant canvary from about 0.050 inches to about 1 or 2 inches. In certainembodiments, the implant can define a central region or void 71. Thecentral region 71 can be configured to minimize contact with sensitiveregions of the body, such as the trigone 9, bladder neck 13, etc. Thecentral region 71 can allow for the passage of urine out through theurethra and to not interfere with normal urination. The selection of thesize of the central region 71, such as the inner diameter of a toroidshaped implant, can be critical in avoiding contact of the intravesicaldevice with the trigone region or bladder neck when the bladder is emptyor nearly empty. Given the typical size of the trigone; toroid, ring,coiled devices, or other shaped devices can have an inner opening ofabout 0.1 inches to 5.5 inches, more preferably about 1.5 inches to 4inches, or more preferably greater than about 1 inch.

In another embodiment, the central region of the implant is traversed byone or more extensions that may further define a central hub. In certainother embodiments, the central area comprises a membrane that is porousor comprises one or more holes that allow for the passage of bodilyfluids. The inner area can be a membrane that can serve as a “platform”of sorts. The area can be perforated in any pattern to allow urine topass through and also serve as a platform for other components such asan infuser, transducer, or coating. The components can be used for,pressure monitoring, drug delivery, electrical pulse delivery, pressurewave delivery etc. The ring itself, hub, central regions or extensionscan contain or deliver therapeutic agents and further comprise a pump,infuser, or other dosing system as provided infra. Alternatively,components of the implant can comprise a transducer, or serve as aplatform for any of the intravesical devices described herein.

As discussed previously, an implant can be at least partiallyexpandable. Expansion facilitates delivery by allowing the implant toassume a first delivery profile for passage through the urethra orsurgical opening in the bladder and to assume a second expanded profileoperable to prevent the implant from entering the trigone region. Insome embodiments, the expanded implant can be characterized by one ormore dimensions greater than the smallest cross-section distance of thetrigone region.

Delivery

One aspect of the disclosure relates to the delivery of an implant.Various instruments and implants are provided herein for theimplantation of medical devices within the bladder via the urethra, opensurgery or percutaneously through the abdomen, back, vagina, bowel, orperineum. In certain embodiments, the implantable medical device maycomprise one or more expandable membrane enclosure or balloon, sponge,attenuator, space occupying member, drug delivery device, datacollection device, nerve stimulation device, wave producing device,vibration producing device, pressure sensing device, chemical sensingdevice, volume sensing device, or a therapeutic device. From thisdisclosure it will be appreciated that although the examples provideddeal primarily with delivery of an implant into the bladder, the methodsand devices herein can be used to provide treatment at sites in otherareas of the body as well. For example, devices can be placed within orproximal to other organs and sites in the body such as the heart, lung,cranium, cardiovascular system, breasts, abdominal area or cavity, eye,testicles, intestines, stomach, etc.

Referring to FIG. 6, there is illustrated one delivery system fordeploying an implant, such as, an attenuation device, into a treatmentsite, such as, for example, the bladder. In general, the delivery system40 is configured to advance the implant 66 (not illustrated)transurethrally into the bladder while in a first, reducedcross-sectional configuration, and to thereafter inflate or enlarge orpermit the expansion of the implant to a second, implanted orientation.The particular configuration and functionality of the delivery system 40will therefore be governed in large part by the particular design of theimplant 66. Thus, as will be apparent to those of skill in the art inview of the disclosure herein, various modifications and adaptations maybecome desirable to the particular delivery system disclosed herein,depending upon the construction of the corresponding implant.

The delivery system 40 comprises an elongate tubular body 42 having aproximal end 44 and a distal end 46. Tubular body 42 is dimensioned totransurethrally access the bladder. Thus, the tubular body 42 preferablyhas an outside diameter of no more than about 8 mm, and, preferably, nomore than about 3-6 mm. The length of the tubular body 42 may be varied,depending upon the desired proximal extension of the delivery system 42from the urethra during deployment. In general, an axial length oftubular body 42 within the range of from about 1″ to about 10″ for adultfemale patients and from about 4″ to about 30″ for adult male patientsis currently contemplated.

The tubular body 42 is provided with at least one central lumen 48extending axially therethrough. Central lumen 48 axially slideablyreceives a filling tube 50, for filling the attenuation device 66.Filling tube 50 is a tubular body 52 having a proximal end 54 and adistal end 58. An inflation lumen 60 extends throughout the length ofthe tubular body 52, and is in fluid communication with a proximal hub56. Hub 56 comprises a connector such as a standard luer connector forcoupling to a source of inflation media.

The tubular body 52 has an axial length which is sufficiently longerthan the axial length of tubular body 42 to allow the proximal hub 56 toremain accessible to the clinician and accomplish the functions ofdeploying and filling the implant 66. In one embodiment, an outertubular sheath (not illustrated) is slideably carried over the tubularbody 42, and is spaced radially apart from the tubular body 52 to definean annular cavity for receiving a rolled attenuation device 66 therein.In this manner, the deflated implant 66 can be rolled around a distalportion of the tubular body 52 and carried within the tubular sheathduring transurethral placement. Once the delivery system 40 has beenproperly positioned, proximal retraction of the outer sheath withrespect to the tubular body 52 exposes the deflated implant 66. A sourceof inflation media is coupled to the proximal hub 56, and media isintroduced distally through central lumen 60 to inflate the implant 66.Following inflation of the implant 66, the delivery system 40 isdisengaged from the implant 66, such as by retracting the filling tube50 with respect to the tubular body 42. A distal stop surface 47 ontubular body 42 prevents proximal movement of the implant 66 as thefilling tube 50 is proximally retracted. Delivery system 40 isthereafter removed from the patient, leaving the inflated implant 66within the bladder.

With reference to FIGS. 6A and 6B, there is illustrated a modifiedversion of the delivery system 40. In this embodiment, a control 62 isplaced at the proximal end 54 of the tubular body 52. The control 62 maybe in any of a variety of forms, such as a handle, knob or pistol grip.The control 62 may be grasped by the clinician, and utilized to axiallyadvance or retract the filling tube 50 within the tubular body 42. Theproximal hub 56 is connected to the tubular body 52 by way of abifurcation 61. As will be appreciated by those of skill in the art, thecentral lumen 60 extends from the proximal hub 56 to the distal end 58.An inflation source 64 such as a syringe filled with a predeterminedvolume of a gas, liquid or other media may be connected to the proximalhub 56.

For patient comfort, the introducer is suitably sized to easily passthrough the urethra (approximately 1 to 8 mm diameter). Visual feedbackis provided to the clinician by means of insertion depth indicatorsalong the longitudinal length of the introducer. The introducer may alsohave a fixed or adjustable depth stop that allows the clinician topre-set the desired insertion depth. One can also determine whether theintroducer has reached the bladder via urine reflux through theintroducer, visually via intraoperative imaging, or via inflating adistal locator balloon after the introducer has been inserted a selecteddistance and pulling back on the introducer until the balloon resistsfurther backward travel through the bladder neck. The distal locatorballoon can be carried within or along the introducer and inflated via aseparate lumen. Locator balloon, buckling or accordion-like expandablesystems can be used as part of any delivery systems described herein.Once the delivery system has been inserted into the urethra to thedesired depth the introducer is then kept in a fixed position and theattenuation device mounted on the distal end of the fill tube is thenextended in the lumen of the bladder. The attenuation device is thenfilled with the indicated volume of media from the attached syringe orsimilar device. Once properly inflated, the attenuation device isreleased from the fill tube using the tip of the introducer as anopposing force disengaging the attenuation device valve from the filltube. The fill tube is then retracted completely into the lumen of theintroducer and the entire delivery system is then withdrawn from thepatient. The attenuation device is left in place for the clinicallyindicated period of time.

One aspect of the present disclosure relates to the delivery of a veryflexible, thin walled device. Delivery of an attenuation device istypically accomplished via a suitably sized introducer or possiblythrough the working channel of an endoscope or cystoscope. However, incertain instances the columnar strength of an attenuation device maymake it difficult to be pushed through such channels. In many situationsit will be desired that the delivery system be atraumatic, and not posea threat of tissue damage.

To facilitate the deployment of the implant, it may be desirable tocompact the implant to fit into a cannulated device or transurethralsheath. This can be done by folding, compressing, rolling, etc. Forexample, folding the implant can shorten the effective length of thedelivery system and compress the implant along one or more axis. As theimplant is filled, it can unfold and assume its intended dimensions.Also, the folds can preferably be oriented such that the initiallyopening side or flap opens upward away from the trigone or is orientedto open in the direction of the dome.

In one example, the implant 66 is folded in half and then in half again.Thus the implant is one quarter of the original size. The folded implantcan then be pulled, pushed, rolled, surrounded and/or otherwise placedwithin and/or connected to a delivery system.

The implant is normally folded on itself along its diameter in order topresent a low profile for insertion into, for example, a patient'sbladder transurethrally. The implant can be wound, rolled-up,compressed, or otherwise folded, all in one or more directions, todecrease the size of the implant for the delivery procedure. Followinginsertion the implant can be inflated via an inflation tube to which itis pre-mounted. After inflating the inflation tube is detached and theimplant is freed.

With reference to the embodiment illustrated in FIGS. 7A and 7B, adelivery system 40 for delivering an implant 66 into the bladder isshown. The implant 66 can be an attenuation device to attenuate pressurewaves in the bladder. The delivery system 40 shown comprises anattenuation device containment tube 386, an inflation tube 382 and anatraumatic tip 378. The attenuation device containment tube 386 is asimple open-ended cylinder. The attenuation device 66 is folded asdescribed previously and inserted into the containment tube 386. An openend of the containment tube 386 would present a potentially traumaticedge to the urethra. In order to prevent such trauma, the open end ofthe containment tube 386 in this instance has a rounded atraumatic tip378. This tip 378 contains slits 388 which, on sliding the inflationtube 382 and attenuation device 380 forward allows the tip 378 to openand deploys the attenuation device 66 from the containment tube 386 intothe bladder.

In use the distal end of the delivery system 40 is inserted through theurethra to an appropriate depth. The attenuation device 66 is advancedusing the inflation tube 382 and releases easily from the containmenttube 386. The attenuation device 66 is inflated, released from theinflation tube, and floats freely in the bladder. Guidance usingultrasound or other imaging modality or position feedback system canalso be employed to help guide the delivery system into the bladder.

In one embodiment, a removable delivery system is used to deliver,deploy, and fill an attenuation device. The delivery system can take theform of the system taught by U.S. Pat. No. 5,479,945, titled “Method anda Removable Device which can be Used for the Self-Administered Treatmentof Urinary Tract Infections or Other Disorders,” issued Jan. 2, 1996,the disclosure of which is incorporated in its entirety herein byreference.

With reference to FIGS. 8A and 8B, there is illustrated onedisengagement sequence for deploying an inflatable attenuation device 66from a delivery system 40. As illustrated in FIG. 8A, the deliverysystem 40 is initially configured with the filling tube 50 positionedwithin the valve 80. The distal end 46 of outer tubular body 42 isdimensioned such that it will not fit through the aperture 82 of valve80. Once the attenuation device 66 has been positioned within thebladder, the attenuation device 66 is inflated through filling tube 50.

With reference to FIG. 8B, the filling tube 50 is proximally retractedfollowing inflation so that it disengages from the valve 80. This isaccomplished by obstructing proximal movement of the attenuation device66 by stop surface 47 on the distal end 46 of tubular body 42. Theattenuation device 66 is thereafter fully disengaged from the deliverysystem 40, and the delivery system 40 may be removed.

FIG. 9 presents another embodiment of a delivery system 40A. Thedelivery system 40A can be used with many different types of implants66, including an attenuation device. As shown, the attenuation device 66has been rolled in preparation for delivery. The attenuation device 66can also be prepared in other ways as discussed above, such as being bewound, rolled-up, compressed, or otherwise folded, all in one or moredirections, to decrease the size of the implant for the deliveryprocedure. The attenuation device 66 in a preferred embodiment is aspherical balloon with a one-way valve.

The delivery instrument or system 40A, shown in FIGS. 9 and 9A comprisesa guide body 2, syringe 64, implant decoupler or advancer 4, meatal stopsurface 6 and transurethral body 8. The syringe or other suitableinflation or injection mechanism 64 may comprise a barrel 10 and aneedle or conduit 12. The needle 12 can be connected to the barrel 10 bya luer connection or other connection mechanism known in the art. Theneedle 12 can be slidably inserted within or along an implant advanceror decoupler 4. The implant 66 can then be connected to the needle 12.In use, the decoupler 4 disengages the implant 66 from the needle 12.Both the needle 12 and decoupler 4 may be slidably carried by or withinthe guide body 2. When connected to the guide body 2, the decoupler 4has an exposed portion 14. The guide body 2 further comprises anadjustable or fixed meatal stop surface 6 and a hollow transurethralbody 8 terminating in a tip 16. The tip 16 can be an atraumatic tip. Thetip 16 can also have slits or perforations 388.

In one embodiment, the implant decoupler 4 is a feature within or alongthe transurethral body 8 that prevents an implant 66 from beingretracted into the instrument or move in a direction other than distallyaway from the delivery instrument 40A. In another embodiment, thedecoupler 4 is advanceable and advances the implant 66 out of, orrelative to, the transurethral body 8 and/or needle 12. The needle 12terminates in a tip 18. The implant 66 can be coupled to the needle tip18 via an engagement mechanism. The engagement mechanism can comprise avalve, such as the valves shown in FIGS. 5-5A, which can be mated to theneedle tip 18. At least a portion of the implant 66 may be carriedwithin or alongside of the transurethral body 8.

The delivery system 40 can impart columnar strength to the implant 66.In some embodiments, for example where the implant is a flexible body,increased columnar strength can be desirable to facilitate delivery ofthe implant in to the body. In some embodiments, the transurethral body8 can impart columnar strength to the implant 66. In certainembodiments, the implant 66 is compressed or folded along one or moreaxis. In some embodiments, the implant 66 is wound, wrapped, coiled,spun, twisted, or spiraled within the transurethral body 8 and/or aboutthe needle 12 or advancer 4 to impart columnar strength allowing it tobe expelled out of or relative to the transurethral body 8.

In FIGS. 10A-G and 11A-C, other examples of portions of transurethralbodies 8 of various delivery instruments 40 are provided. In FIG. 10A, atransurethral body 8 comprises a tubular, cylindrical, hollow orcannulated member with a lateral opening, window or port 20 and acurved, rounded, or blunt distal tip 16. The opening 20 can be oval(FIG. 10A), circular, rectangular, slit-like (FIG. 10B), oblong (FIG.10C), teardrop shaped, biased and can further comprise a flap, door orretractable cover 22 (FIG. 10D).

In some embodiments (not shown), the transurethral body 8 is formed as awrap covering the implant 66. The wrap can be shrunk around the implant66, wound around the implant 66, or the wrap can be applied as acoating. In some embodiments, the implant 66 is the transurethral body8, in this embodiment the implant 66 can be compressed to create a smallprofile and be comprised of a lubricious material to facilitatetransurethral or percutaneous travel.

The tip curve can be biased (FIG. 10E) or symmetrical (FIG. 10A). Atleast a portion of the transurethral body 8 itself and instrumentelements carried within or along it can be rigid, flexible, curved orhave multiple curves to facilitate placement within and beyond theurethra to deliver to different sites within the bladder such as theback wall, dome, rugae of mucosa tissue, trigonal area, ureteralopenings, internal or external urethral openings, and internal orexternal urethral sphincters. Also shown are transurethral body members8 having oblong windows 20 providing for the preferential or biasedopening or expansion of an implant 66. In one embodiment, the opening 20biases the distal expansion of a balloon implant 66 such that theimplant 66 is delivered laterally and distally at the same time.

In another embodiment, a portion of the transurethral body 8 and/ordecoupler 4 is comprised of a shape memory material that when heated bythe human body after insertion assumes a second shape, such as, bent orcurved. The transurethral body 8 and/or decoupler 4 can also be operableto deliver the implant 66 within the upper or domed section of thebladder or deflect off of the back wall of the bladder.

As shown in FIGS. 11A-C, a transurethral body 8 can have double ormultiple openings 20. Shown are two openings 20 at a distal portion ofthe transurethral body 8 and an optional connector passage 26 for acoupled implant. The implants 66D shown are two balloons coupled by aconnector 24 forming the shape of a dumbbell. The connector 24 maysimply be an extension of the balloon membrane, suture, or a fluid orgas conduit.

Turning to FIGS. 12A-C, various syringe 64 and transurethral body 8elements are presented oriented in different positions relative to theguide body 2 of the delivery instruments 40B, 40C. Angling the syringe64 offset to the guide body 2 may be advantageous to provide for a morevertical syringe barrel 10 orientation during delivery.

For example, in some embodiments it is desired to inject a media havinga gas component and a liquid component into the implant 66. The liquidcomponent can be very small compared to the gas component. In someembodiments, the media can comprise 0.5 cc liquid PFC and 25 cc of air.In the orientations shown, the liquid portion will tend to resideproximate the needle or conduit 12 and be delivered first into theimplant and then followed by the air or other gas component remaining inthe barrel. This feature can be critical when delivering small amountsof liquid relative to the volume of gas.

In the embodiment of FIG. 12C, the barrel of the syringe is coupled to aflexible conduit 12 terminating in a tip or implant coupling mechanism18 which may be flexible or rigid. In some embodiments, the syringe andflexible conduit is used in the configurations of FIGS. 12A and B.

Various tip or implant coupling mechanism 18 profiles are presented inFIGS. 13-13E. The tips can be mated with corresponding female portionsof implant valves. FIG. 13 shows the needle 12 in the valve 80 of theimplant 66. An opening 28 in the needle tip is also shown. FIGS. 13A-Eare taken along line A-A to show the cross-section of the needle 12. Ascan be seen, the cross-section can be any of many shapes, including,circular, flat, oval, rectangular, rounded rectangular, and otherpolygons. In some embodiments, the needle tip can assume a first shapeand a second shape such as that shown in FIG. 13E. The first shape canbe used when inflating the implant 66 and needle tip can assume thesecond shape after inflation or upon sealing of the valve 80. The needle12 tip can further comprise a raised rib or coupler mated to the balloonto prevent backflow during inflation or a groove or recess operable toaccept an adhesive, polymer, or flexible material such as silicone toform a compliant fit with the balloon

Turning now to FIGS. 14A and B, an embodiment of transurethral body 8and distal tip 16 is shown. Implants 66 may be advanced out of orthrough the transurethral body 8 at various points along its long axisor distal end. In some embodiments the tip 16 is open, perforated,pointed, blunt, and/or rounded. One or more perforation, slit, window,door, flap, port, and may be positioned along the transurethral body 8to facilitate the expulsion or expansion of the implant 66 within orcarried by the transurethral body 8. In various embodiments the implant66 is expelled from the transurethral body 8; in other embodiments theimplant 66 expands and breaks or parts the perforations 388 along thetransurethral body 8 or expands a slit 388 or elastic opening.

In FIG. 14C, a transurethral body 8 is shown wherein the implant 66 isat least partly exposed to form a tip. As explained previously, theimplant 66 can be compressed or wound and may be coated, lubricated orbuilt up with a biodegradable substance to ease insertion into thebladder.

With reference to FIGS. 15A-18C, various steps of a delivery sequenceare shown, including optional steps to improve the outcome of thedelivery. As an initial step, the amount of fluid in the bladder may bedetermined. This may be done, for example, cystoscopically, via imaging,or via a catheter. In FIG. 15A, a relatively empty bladder 5 is shown.Preferably, there will be at least 100-500 cc of fluid present withinthe bladder 5 for implantation. In some embodiments, there will be aminimum of 200 cc of fluid in the bladder 5. According to someembodiments, liquid or gas is added to the bladder 5 to ensure that atleast 100-500 cc of liquid and/or gas is present within the bladder 5during implantation (FIG. 15B).

Optionally, a cystoscope or probe can then used to determine the lengthof the urethra 7 and/or the distance from the internal urethral openingto the back wall of the bladder. The adjustable meatal stop surface 6 ofthe guide body 2 is adjusted such that the transurethral body 8 willextend beyond the inner urethral opening to a select depth.Alternatively, a device having a fixed meatal stop feature may beappropriately selected from among multiple sized devices based on thepatient's anatomy.

A delivery system 40, such as those depicted in FIGS. 9-14, may be usedin the delivery procedure. The delivery system 40 may optionallycomprise a syringe 64 containing a gas such as air and a small amount ofliquid perfluorocarbon (PFC) or other liquid with a high vapor pressureand/or therapeutic agent. The use of an implant with PFCs and/or otherliquids with a high vapor pressure is explained in more detail below.

The delivery system 40 can be prepared by filling the syringe 64 withthe desired amount of fluid and/or gas (FIG. 16A). In some embodiments,the syringe can be filled with a certain amount of liquid PFC and acertain amount of air. In some embodiments, the amount of air cancomprise about 1-100 cc. In some embodiments, the amount of air cancomprise about 15-25 cc. In some embodiments the amount of fluid PFC cancomprise about 0.1-2 cc. In some embodiments, the amount of fluid PFCcan comprise about 0.5-1 cc.

After the syringe is prepared, it can be connected to or inserted intothe rest of the delivery system 40 (FIG. 16B). In some embodiments, suchas that shown in FIG. 9, the delivery system 40 and implant 66 can beprepackaged and assembled. The syringe 64 can be disconnected so that itmay more easily be filled. The filled syringe 64 can then be connectedto the needle or conduit 12 via a luer connection in preparation forimplantation of the implant 66.

As shown in FIG. 17A, the transurethral body 8 is then inserted into theurethra. In some embodiments, the meatal stop 6 will abut the meatus todetermine how far the transurethral body 8 will advance into the bladder5. In other embodiments, such as delivery systems 40 without a meatalstop 6, the physician may use markings on the side of the device orother devices to determine how far to advance the transurethral body 8.The tip 16 of the transurethral body 8 can be deflected off of the backwall of the bladder (FIG. 17A) or the length of the transurethral body 8can be dimensioned such that the tip 16 is incapable of reaching thewall. Alternatively the transurethral body 8 can be curved (FIG. 17B-C),bent, biased, flexible, articulable or comprised of a shape memorymaterial such that upon full insertion the distal end extends upwardtoward or within the dome of the bladder.

Once the desired implant location is reached, some embodiments ofdelivery system 40 may optionally be oriented such that the distal tip16 or opening 20 is in a desired direction or position relative to thebladder to release and inflate the implant 66. This may include rotatingor tilting the device 40. For example, with an opening 20, shown in FIG.17C, the implant can be delivered in a way that is away from the backwall of the bladder or from tissue in the dome area.

Once in the proper position and/or orientation, the implant 66 can beadvanced into the bladder 5. This can be done in many different ways aswill be shown. In some embodiments, such as with the delivery device 40of FIG. 9, the advancer 4, syringe 64, needle or conduit 12 and implant66 can be advanced within the guide body 2 and transurethral body 8.This advancement can break or opening the slits or perforations 388 onthe tip to allow the implant 66 to exit the delivery instrument 40 (FIG.17D). In some embodiments, the implant 66 can exit the tip 16 through anopening 20. The plunger of the syringe 64 is then depressed, to deliverthe media, such as fluid and gas, into the inflatable device 66. Theconduit or needle 12 is then retracted, thereby disengaging andreleasing the implant 66 into the bladder. The valve 80 of the implant66 in which the needle 12 had been inserted also closes and retains themedia within the implant enclosure.

In some embodiments, the implant 66 may or may not be advanced.Inflating the implant 66 can cause the implant 66 to expand and canforce the implant to exit the transurethral body 8. In this way, theinflatable device or implant 66 can exit the window 20 or slit 388 inthe tip 16. Also the perforations 388 can be forced open along thetransurethral body 8 by expanding the implant 66.

In some embodiments, inflating the implant 66 causes the implant toseparate from the delivery instrument 40. In some embodiments, relativemovement of the advancer 4 and needle or conduit 12 (either movingforward or backward relative to the other) causes the implant 66 todisengage and the implant valve 80 closes. Once the implant has beenreleased, the delivery instrument 40 can be withdrawn from the bladderand the urethra.

In certain embodiments, the implant 66 can be dislodged from thedelivery instrument 40 by relative motion of needle or conduit 12 towhich the implant 66 is attached and the advancer 4 encompassing theneedle 12 in a shearing motion.

In another embodiment, the implant 66 can be deployed as a long,straight tube which coils as it leaves the deployment sheath due to apre-set pattern, set in either the shell of the implant or a stiffeningmember with shape memory.

In another embodiment, in which the inflation media is comprised of aliquid-gas mixture, a pre-loaded syringe 64 or forward filling of theneedle or conduit 12 is provided. The liquid portion can be pushedthrough the gas portion of the mixture. Also, the liquid can be kept inthe open flow path with the use of a flexible adapter or valve thatprevents the liquid from falling out of the conduit 12 if the syringe 64is removed to fill with gas in a two step sequence.

In yet another embodiment, a flexible implant 66 is compressed,accordion-style and is operable to spring forward during deployment,inflation of the implant 66, or release of a compressing member.

In a further embodiment, an implant 66 is deployed and partiallyinflated with a small portion of liquid. In this embodiment, the liquidhas the ability to create a negative vapor pressure gradient whichwould, over time, force gas from the external liquid environment intothe implant 66, thus inflating it.

With reference to FIGS. 18A-H, one particular non limiting deliverymethod will be explained. Other embodiments can comprise one or more ofthe steps outlined below. Each step A-H refers to the corresponding FIG.18A-H. In step A, the bladder is checked to ensure that a minimum of 200cc of fluid is in the bladder 5. Additional fluid is added if necessary.Air and water are examples of the fluid. Other embodiments can includedifferent amounts of fluid. In step B, the transurethral body 8 islubricated and inserted into the urethra 7. In step C, the deliversystem 40 is tilted down such that the tip 16 is pointed upwards at thedome of the bladder. In step D, the advancer 4, syringe 64, implant 66and needle 12 are advanced while rotating clockwise and the guide body 2and transurethral body 8 are maintained in a stationary position. Thisinserts the implant 66 into the bladder 5.

In step E, media is injected into the implant 66, expanding the implant66. In this embodiment, the media includes an amount of liquid PFC andabout 15 cc of air. In step F, the advancer 4 is disconnected from thesyringe 64 and needle or conduit 12. In this embodiment, the advancer 4is connected to the syringe via a luer connection, thus rotating thesyringe 64 while holding the advancer 4 stationary can disconnect theluer connection. In step G, the advancer 4 and guide body 2 are heldstationary while the syringe 64 and needle or conduit 12 are retracted.Here they are retracted about one inch. This releases the implant 66from the delivery instrument 40 into the bladder 5. Finally, thedelivery instrument 40 is removed from the urethra 7 and discarded instep H.

Some delivery methods can include delivering the implant 66 away fromthe trigonal area. This can include identifying the back wall of thebladder to ensure that the implant 66 is not delivered in the trigone.This can also include expanding or unfolding the implant away from thetrigone. This can also include ensuring that a minimum amount of fluidis in the bladder so that a buoyant implant, such as an inflatableimplant, will naturally move away from the trigone.

Suitable materials for the guide body 2, transurethral body 8, conduit12, needle 12, and tip 16 can include: stainless steel, titanium,plastic, nitinol, PEEK, polyimide, polysulphone, fluorinated polymers(PTFE, PFA, FEP, ETFE, PVDF, CTFE), polyethylene (high or low density),polyether block amide, polyester terethalate or elastomers of PET orPBT, ABS, other impact modified styrenics, polycarbonate or copolymersof polycarbonate, braided forms of any of these, reinforced forms of anyof these, etc.

Coatings or impregnation agents may also be applied to or integratedinto the material above to improve the delivery or treatment outcome.Alternatively such agents can reside in an enclosure or a reservoir andelute out of the device over time. Such agents can include: silver, PET,silicone, active biologic compounds, aqueous hydrogels, butyl rubbers,metal coatings, nano crystallized silver based antimicrobial coating,polyvinylpryrrolidone based coatings, drug coatings including duloxetinehydrochloride, nerotranmitters mediating drugs, analgesics, antiseptics,antibiotics, incontinence treatment drugs, anti-cancer drugs, cystitistreating drug, oxybutynin, anti microbial agent, lubricious agent,anti-incontinence drug, etc.

The diameter of the transurethral body 8 can range from about 2-8 mm or6-24 french. The length of the transurethral body can range from to 2-8cm in females and longer for males. The angular offset of thetransurethral body 8 relative to the guide body 2 can range from 0 to180 degrees preferably about 0-30 degrees. The angular offset of thetransurethral body relative to the syringe barrel 10 can range from0-180 degrees preferably 70-110 degrees.

The delivery instrument 40 used for males may optionally have a bent tipto aid in navigating through the urethra as it passes through theprostate. Generally it is desirable to have a more flexible deliverydevice for men because of the longer urethral length and the fact thatthe urethra “bends” proximal the prostate. Preferred systems benefitfrom the ability to “flex” while bending around corners, and resist“kinking.” This can be accomplished by a combination of wall thicknessand/or having a coiled spring in the wall or a braided structure.

As discussed, an implantable pressure attenuation device can inflatefrom a first, deflated configuration to a second, at least partiallyinflated configuration. Various transformable mediums can be used toinflate the housing of the attenuation device from a deflatedconfiguration to at least a partially inflated configuration. In someembodiments, the device is self-inflating.

Removal

The implant 66 is preferably removable from the implanted site, such asthe bladder. Removal may be accomplished in any of a variety of ways,depending upon the construction of the implant. Preferably, removal fromthe bladder is accomplished transurethrally.

Generally, methods of removal from the bladder will include one or morethe following steps: identifying the location of the implant 66 withinthe bladder; engaging the implant; in some embodiments, compromising theintegrity of the implant 66 to remain inflated and deflating the implant66; compressing the implant 66; and removing or allowing the implant 66to be passed out of the bladder. Alternatively, the implant 66 may beabsorbed, dissolved or degraded within or by the bladder or urine.

For example, according to some methods the following steps are taken toremove an inflated implant or balloon 66 from the bladder with referenceto FIGS. 19A-E. First, a cystoscope is inserted into the bladder. Thebladder is drained and the implant is visually located (FIG. 19A). Thena retrieval device, such as any of those described below, is insertedinto the cystoscope to engage the balloon 66 (FIG. 19B). The balloon 66is then deflated by squeezing or compressing the balloon 66 with theretrieval device while pressing the balloon against the wall of thebladder (FIG. 19C). Next, retract the retrieval device and the balloonto the end of the cystoscope (FIG. 19D). Finally, the cystoscope and theballoon are removed together (FIG. 19E).

Various steps and related treatment and retrieval devices will now bediscussed.

Locating the Treatment Device

Locating an implant 66, such as an intravesical treatment device withinthe bladder, can be an active or passive process. For example, thesurgeon actively searches for the treatment device 66 visually orblindly, probes around the bladder and receives tactile or otherfeedback from an instrument. Alternatively, a magnetic element of theimplant 66 or a vacuum device can be used to blindly locate the device66.

A preferred method for inspecting the bladder to locate the implant 66involves the use of a cystoscope. A cystoscope generally has a workingchannel for inserting other instruments such as a forceps or grasper.Instead of a cystoscope, a cannula, sheath, or tube may be used. Such aninstrument can be fitted with or carry a photo-sensor that can be usedto provide visual feedback. For example a sheath can carry opticalforceps or a grasper instrument with a distal mounted photo sensor. Thephoto sensor may be built into the end of the device such as a CMOS orCCD sensor or it may be at the proximal end of the device or separatefrom the device with the use of a fiber optic pathway.

In one embodiment the implant 66 comprises stripes, dots, geometricshapes, characters or other non-anatomical pigmentation (pink, red, andwhite) to improve its visibility within the bladder. Further embodimentsmay comprise surfaces with reflective or shiny elements or infrared,ultraviolet, fluorescent signature colors to facilitate visualrecognition by the person removing the device. Alternative embodimentsof the implant 66 may optionally include enhancements that may bedetected or located with appropriate instrumentation. Such implantenhancements can include an RFID chip or transmitter, radio opaqueelement, charged surface or portion, selected electrical resistancedifferent than bladder tissue or urine, magnetized surface or portion,or comprise a ferrous material.

FIG. 20A, illustrates the step of locating an implant 66 with acystoscope or other cannulated instrument 30. A photo sensor or opticalelement 32 is shown that can be used to locate the implant 66 within thebladder. The implant 66 can also include an enhancement or distinctivefeature 34, as described above which can help the physician to find theimplant.

Rather than actively searching for the device to locate it, othermethods can be employed to cause the device to migrate to or remain in aselected location. In this way, the implant 66 would necessarily bewhere the surgeon inserts an instrument. For example, emptying orfilling the bladder with liquid and or gas such that the device floatsor sinks to a known location. Alternatively, the implant 66 can becompressed proximal to or adjacent the urethra or trigonal region whenthe bladder is completely voided. Also a tether or anchor could be used.

In another embodiment, the bladder is completely evacuated with a vacuumor suction device. Alternatively, the vacuum device can be used to drawin the implant 66 to the suction device. The tip of some embodiments ofa suction device can comprise a cage or filter. The cage can be dome orspherical shaped. The cage can prevent bladder tissue from entering thesuction device but permit at least a portion of an intravesical device66 to enter the suction device. The suction device may optionallyinclude a piercing element such as a needle or heating element todeflate implant.

In some embodiments, as shown in FIG. 20B, a vacuum or suction tube 36is passed through a cystoscope or cannulated device 30. Upon locatingthe implant 66 the suction tube 30 engages the implant 66 with suctionforce. When more suction is applied the implant 66 is brought intocontact with the tip of the suction tube 36 or cannula 30 causing theimplant 66 to tear. The content of the implant 66 is then suctionedfollowed by the implant 66 which either passes through the suction tube36 or is engaged by it. The suction tube 36 and implant 66 are thenretracted within the cannula 30 out of the urethra.

In another embodiment, an implant 66 is anchored or tethered to aselected site along or within the wall of the bladder (FIG. 20C),ureters or urethra. In this instance, the surgeon need only return tothe implantation site and retrieve the implant. FIG. 20C further shows atether or anchor 38 connected to an implant 66 deployed in the bladderjust beyond the neck of the bladder in the trigonal region.

In yet another embodiment, the tether 38 can optionally be placedpartially within the urethra or extend outside the body beyond theurethra. In yet another embodiment, a tether 38 is retracted within orencapsulated into the wall, surface, or mass of the implant and thenreleased at approximately the desired time of removal to facilitateretrieval of the device. The release of the tether can be timed using abioabsorbable polymer casing, an electronic timed device, or in responseto an external stimulus such as radiofrequency energy, x-rays or otherradiation. The tether 38 can be used solely as a means to capture,locate or withdraw the implant 66 or it have a dual function wherebytension or force applied to the tether can first cause the device todeflate or otherwise collapse, compress or take on a configuration thatwill facilitate removal; and then later be used as a handle to locate,capture and/or remove the implant 66.

Deflating or Compressing the Implant

Certain intravesical treatment devices comprise expanded or inflatedcomponents to provided flotation, fixation, and attenuation, as drugdelivery platforms or to prevent the device from migrating into certainregions of the urethra or bladder such as the trigone region.

Piercing or destroying the capacity of the implant to remain inflated orhold a gas or liquid can involve the step of breaking, stretching,disrupting, melting, burning, decomposing, or altering the chemicalstructure of at least a portion of the implant. Such techniques mightemploy a needle, barb, cutting blade, hooked probe, auger, morcellator,wetjet, laser, RF emitter, suction tube, ultrasonic instrument,microwave, or thermal or cryogenic element.

In one method a retrieval tool 86 is fit through the working channel ofa cystoscope, catheter or other cannulated device 30, as in FIG. 21. Theretrieval tool 86 may comprise an elongate shaft terminating in a handleat one end and one or more engagement members at the opposing end. Thehandle may comprise one or more actuators such as a finger ring,trigger, lever, or button for controlling one or more engagement memberssuch as a pincher, grasper, tine, or blade element, grasper-like handtool, forceps, pronged, electrode or hooked device. The engagementmembers may be opposable, sharpened, hooked, barbed, serrated, or havean adhesive or magnetic site. The actuators may be linked to theengagement members via a direct mechanical linkage, fluid pressure(pneumatic, hydraulic or other) or through circuitry or other modalitycarried by or along the shaft. In one embodiment, such as that shown inFIG. 21, the engagement member assembly may be passable through thecannula 30. In another embodiment, a retractable sleeve is mounted atthe distal end of the elongated shaft. In any of these embodiments, theengagement members may be compressed or shielded prior to deployment outof the catheter, hollow shaft, or sleeve. The shaft of the removaldevice can also comprise a camera or working channel for deliveringother instruments, passing or draining fluids and/or gases.

Teeth or similar structures of a retrieval tool or grasper 86 can beused to bite, tear, cut, puncture, rip, and/or otherwise disturb themechanical integrity of the implant material. The teeth, hooks, prong orprongs of the grasper 86 can be drawn along the surface of the implant66 to score, rip, or otherwise compromise the ability of the device toremain inflated. Two or more graspers 86 can engage the implant 66 andcan then be advanced in opposing directions, or one relative to theother, to tear open the implant 66.

Graspers 86 can have separate shafts or be two, two-prong graspers 87,89 that have independent motion. Alternatively, graspers may havesingular control but move at different rates or one or more grasper canbe stationary while one moves, as in FIG. 22A. In one embodimentinvolving four graspers, all four graspers could initially grab theballoon. Upon retraction, two of the graspers move faster than the othertwo thereby creating relative motion and ripping the balloon. Severalother designs are envisioned where there is at least two independentlycontrolled features or, alternatively, two features that exhibitrelative motion with singular control.

Alternatively, the grasper 86, while engaged to the inflated device 66may be retracted into the cannula 30 such that the implant 66 is shearedopen against the outer edge of the cannula 30. The implant 66 may thenbe further retracted into the cannula 30 such that the distal tip of thecannula 30 acts as a fulcrum and is operable to at least partially foldor compress and at least partially deflate the implant 66 as it isretracted within. The cannula 30 may alternatively comprise anextendable or fixed needle or barb 88 proximal its tip wherebyadvancement of the cannula 30 or needle 88 will puncture the implant 66.

Alternatively, the shaft of the retrieval tool 86 itself may be used asa fulcrum such that the retraction of the tool head into the shaftcauses the implant 66 to become compromised. In any of these cases theend of the shaft, working channel or cannula may be optimized fordeflating the implant 66. For instance, the end of the shaft may besharpened, cut at an angle or both to facilitate penetration of theimplant 66. The leading edge can also be serrated, heated, or rotated tofacilitate penetration.

In another embodiment, the prongs for the grasper 86 may be cannulated90 so that attaching a vacuum source to the prongs facilitates theremoval of the media from the implant 66. For example, as shown in FIG.22B, a cannulated prong 90 can have a sharp end to cut the implant 66and then a vacuum can be applied through the cannulated prong 90 todrain the media from within the implant 66. In another embodiment,suction is applied to the shaft of the removal device. In this case, theremoval tool head grabs and tears the implant 66, bringing it intocontact with the removal tool shaft. Suction is applied to the shaft toremove the media from the implant 66.

In another embodiment, suction is applied to the entire bladder througha working channel or tube. In a further embodiment, a mechanical basketor cage, that may also capture or engage the implant 66, is contractedor reconfigured to compress the implant 66 along one or more axis. Themechanical cage can have a needle at the distal end pointed proximallyto puncture the implant 66 as the cage is pulled into the device shaft.A hollow needle would allow deflation therethrough during compression.

As will be explained in more detail below, some embodiments provide aremoval instrument that uses electrical energy to melt or burn theimplant 66 to thereby deflate the device. For example, the instrumentcan include a resistive element to heat the implant 66. Suitable devicesfor performing these tasks can be fit through the working channel of acystoscope or other similar single or multi-lumen device 30, insertedseparately through the urethra, or inserted percutaneously from outsidethe body through adjacent tissues and through the bladder wall. Suchdevices can be carried in, along, or mounted along or at an end of acystoscope, probe, hand tool, guide body, cannula, tube, hose, or otherinstrument described herein.

An alternative embodiment for destroying the capacity of the implant 66to remain inflated would involve instilling into the bladder a liquidchemical that causes all or a portion of the implant 66 to dissolve andthereby facilitate its deflation, and/or compression.

Similarly, in another embodiment, an inflated implant 66 captured with a“lasso” or loop device can be compressed with the tightening of theloop. Optionally, in this embodiment, the lasso or loop can contain aneedle pointing into the center of the loop to puncture and/or applyvacuum to speed the deflation of the implant 66. Finally, in yet anotherembodiment, the doctor or clinician presses within the vagina againstthe bladder to actively expel the contents of the implant 66. Similarlythe doctor or other clinician can use a tool or instrument to press uponthe implant 66 to compress it and expel its contents.

Once the integrity of the implant 66 to hold liquid or gas has beencompromised, the implant 66 can be left or allowed to deflate over timeor actively caused to at least partially deflate by compression or byvacuum with the removal device. Thereafter the device can be withdrawnwithin or carried by the removal device. Thereafter both devices canthen be withdrawn together out of the bladder and urethra.

Implant Enhancements to Facilitate Retrieval

Implant retrieval can be a function of location, access, and ease ofengagement. Accordingly, implant shape and surface pliability may beoptimized for grasping, engaging, and/or puncturing. Though someintravesical implants described herein may be lubricated, or adapted torotate or deflect off of folds in the bladder, other features describedherein may enhance a surgeon's ability to retrieve the device. FIGS.23A-F show various implants with optimized features including: a spiral(FIG. 23A) or coil (FIG. 23B) shaped implant, a toroidal (FIG. 23C) ortriangular (FIG. 23D) shaped implant, a implant that comprises amagnetic or ferrous element, an implant with one or more loops or tabsfor hooking the implant (FIG. 23E), a implant with an outer ring 92 andspokes 94 (FIG. 23F), an implant with a tail or tether (FIG. 23G), andan implant with an anchor that is anchored to a selected site within thebladder (FIG. 20C).

In another embodiment, shown in FIG. 23H, the implant 66 can be shapedas a toroid with interconnected central spokes 94. A removal device 150is used wherein a hooked probe is extended out of a working channel of acatheter 30. The hooked probe can engage one of the spokes 94. Uponretraction of the hook, the implant 66 is forced into contact witheither the cannula 30 or the bladder wall. This force can cause aportion of the implant to break open, initiating deflation of theimplant 66. The implant 66 is then left behind within the bladder tonaturally pass or is retracted through the catheter 30 as describedherein.

In certain embodiments, the intravesical implant 66 may first bedeflated and then retrieved by a grasper, suction, loop, hook or otherdevice that would otherwise not be able to engage the implant in itsinflated state.

Implant Enhancements to Facilitate Deflation

Implants having a predetermined dwell time after which they areautomatically voided advantageously eliminate the need for a removalprocedure. Such temporary implants 66 can be manufactured in a varietyof ways, such as through the use of bioabsorbable or permeablematerials. One or more embodiments of implants 66 provided herein can becomprised at least partially of a biodegradable material such that aftera certain time period lapses the device deflates and is passed ortotally degrades in the bladder. For example, the implant 66 can have awall, seam, valve and/or other parts thereof made from an absorbablematerial. As used herein “absorbable” means any material which willdissolve, degrade, absorb or otherwise dissipate, regardless of thechemical mechanism, to achieve the purpose recited herein. As soon asone or more “fuse” components of the implant 66 is absorbed, the implant66 will deflate through the resulting opening and can be expelled duringnormal voiding.

Alternatively, light, energy, or a chemical or agent such as a solventcan be injected into the bladder to react with the implant 66 and causea portion of it to degrade or come apart, e.g. unseal a seam or flap,thereby allowing the gas within to escape. Similarly, the pH of thebladder can be changed via the delivery of a chemical or agent in thebladder to cause at least a potion of the implant 66 to degrade or comeapart and cause deflation. Alternatively, the agent or application ofenergy can cause a flap to release a loop, tether, or engagement orretrieval member so the implant 66 can be more easily retrieved.

The resulting deflated components from any of the foregoing time limitedembodiments can thereafter either be expelled during normal voiding, orcan remain in the bladder in a deflated state until removed using aremoval system.

In one embodiment, the material or portion of the inflatable container68 (FIG. 5) is made from a gas permeable material. Over time gasdissipates from the inflatable container and the container's likelihoodto pass through the urethra and be spontaneously voided increases. Inone embodiment, the attenuation device is filled with approximately 20ml of gas and the attenuation device's material allows approximately 15ml of gas to permeate out of the attenuation device over certain timeintervals, such as, for example, one, three, six, or twelve months. Oncethe volume remaining is less than approximately 5 ml, the attenuationdevice is normally voided.

The predetermined dwell time within the bladder can be influenced by avariety of design factors, including the formulation of the absorbablematerial and the physical shape, thickness and surface area of theabsorbable component. A variety of absorbable polymers which can be usedare known in the absorbable suture arts. As will be further discussed,the use of a high vapor pressure media element can be used to provide apredetermined dwell time or programmed deflation for various devicesdescribed herein.

The ideal material or device can be optimized through routineexperimentation taking into account the attenuation device design andthe desired indwelling time period. Attenuation devices may be timerated, such as 15 days, 30 days, 45 days, 90 days, 180 days or other asmay be desired. The deflated and or partially dissolved attenuationdevice will be transurethrally expelled within a few days of theexpiration of the rated time period from the time of implantation.

Other embodiments might employ a programmable device that over timecauses failure of the intravesical implant's 66 ability to remaininflated. In other embodiments the implant 66 responds to an externalsignal and deflates or changes shape. Such implants 66 can compriseMEMS, RF devices, and other electronic devices known in the art.

Further details and embodiments of retrieval devices and methods willnow be described.

One or more embodiments of retrieval tools described herein may beoptimized to better transmit linear and rotational force, providetactile feedback, and function in the working channel of a cystoscope.Bending stiffness, torsional stiffness, coefficient of friction of theshaft outer surface and the inner surface in contact with a pull cable(where a cable is used), and column strength should be considered indesigning such instruments. One method for designing higher torsionalstiffness with less effect on bending stiffness is to use metal braid inan elastomeric shaft. The braid can absorb torsional stresses whileadding less to bending stiffness than, for example, using at stiffershaft material. Selecting instrument components with low coefficients offriction (COF) is useful in lowering the forces required to operate thedevice and lessen the requirements of column strength and torsionalrigidity. The coefficient can be lowered by using low COF materialseither as the whole of the shaft or as a coating on the inside diameter,outside diameter or both. Low COF materials known to impart thesedesired properties include the fluorinated polymers, polyethylene, andhydrophilically coated polymers. Braid materials can include stainlesssteel, titanium, nitinol aramid or other high tensile modulus material(Young's Modulus greater than 500,000 psi). Shaft materials can include,PEEK, polyimide, polysulphone, fluorinated polymers (PTFE, PFA, FEP,EPTFE, PVDF, CTFE etc.), polyethylene (high or low density), polyetherblock amide, other copolymers of polyamide, polyamide 11, polyamide 12,polyester terethalate or elastomers of PET or PBT, ABS, other impactmodified styrenics, polycarbonate or copolymers of polycarbonate,braided forms of any of these, reinforced forms of any of these,combinations of any of these. The ideal flexural modulus for the shaftwould be in the range from 20,000 psi to 600,000 psi.

Example 1-Retrieval Loop

Referring to FIG. 24, there is illustrated a side elevational schematicview of one embodiment of an intravesical removal system. This removalsystem 150 is adapted to retrieve the inflated attenuation device 66 asdiscussed elsewhere herein.

The removal system 150 comprises an elongate tubular body 152 whichextends between a proximal end 154 and a distal end 156. Tubular body152 is dimensioned to transurethrally access the bladder. In oneembodiment, the removal system 150 is adapted for use in conjunctionwith standard urological cystoscopes (e.g. approximately 14-24 French),having minimum working channels of approximately 1.8 to 6.0 mm. For thispurpose, removal system 150 in one embodiment has an overall length ofapproximately 76 cm and a useable length of approximately 60 cm.

The tubular body 152 may be manufactured in accordance with any of avariety of techniques well understood in the catheter and other medicaldevice manufacturing arts. In one embodiment, tubular body 152 isextruded from a biocompatible material such as PTFE, having an insidediameter of approximately 0.05-0.1 inches and a wall thickness of about0.01 inches.

The proximal end 154 of tubular body 152 can be connected to a Y-adaptor158. Y-adaptor 158 carries a control 160 for controlling the retrievalsystem as will be described. Control 160 in the illustrated embodimentcomprises a thumb ring 162 which is slideably carried with respect to apair of finger rings 164. Axial movement of the thumb ring 162 withrespect to the finger rings 164 enlarges or retracts a retrieval loop166 extending distally from distal end 156 of tubular body 152.Retrieval loop 166 is adapted to surround the inflated attenuationdevice 66. In one embodiment, the loop 166 has an enlarged diameter ofabout 27 mm, and comprises a wire such as 0.016 inch diameter stainlesssteel cable wire.

In use, the loop 166 is opened once the distal end 156 of the tubularbody 152 has reached the bladder. The loop 166 is positioned around theattenuation device 66, and the proximal control 160 is manipulated totighten the loop 166 around the attenuation device 66. After theattenuation device 66 has been securely grasped by the loop 166, adeflating tube 168, preferably having a sharpened distal tip 169thereon, is distally advanced through the wall of the attenuation device66. Distal advancement of the deflating tube 168 may be accomplished bydistally advancing a proximal control, such as control 172. The distaltip 169 is in fluid communication with a connector such as a standardluer adaptor 170 through a central lumen (not illustrated), so that anempty syringe or other device may be connected to the connector 170 andused to evacuate the contents of the ensnared attenuation device 66. Inother embodiments, the contents of the attenuation device 66 are allowedto empty into the bladder. As the attenuation device 66 is deflated, thecontrol 160 may be manipulated to pull the collapsed attenuation device66 into the distal end 156 of the tubular body 152. The removal system150 having the reduced attenuation device 66 therein or carried therebymay be transurethrally removed from the patient.

A wide variety of modifications can be made to the foregoing removalsystem 150. For example, the proximal controls 160 and 172 may becombined into a pistol grip or other configuration. Controller 172 orcontrol 160 may additionally control deflection of the distal end 156 ofthe tubular body 152, or control rotation of the plane of the loop 166.In general, the removal system 150 preferably accomplishes the basicfunctions of enabling the location of the attenuation device 66,capturing the attenuation device, reducing the attenuation device insize and removing the attenuation device from the bladder. The capturingstep may be accomplished by visualizing the attenuation device throughthe urological cystoscope, or by “blind” techniques, such as, forexample, light reflectance, impedance, suction, ultrasound, passiveinduced microchip, or the magnetic locator.

Example 2-Grasper

An implant removal system 150, according to certain embodiments cancomprise a grasper 86. The grasper 86 can use prongs or jaws to engagethe implant 66 and to assist in the removal of the implant 66.

Steps of a method using the grasper 86 are illustrated in FIGS. 25A-D.The bladder can optionally be drained and the implant 66 located eithervisually or otherwise. A cannulated access device 30 is inserted intothe urethra. When the tip of the catheter is passed into the bladder asmall balloon or anchoring member may be deployed to fix the catheter 30in place (not shown). The grasper 86 is then advanced through thecatheter 30.

Referring to FIG. 25A, the grasper 86 engages the implant 66. Theoptical instrument 32 shown can be used to locate the implant 66. Insome embodiments, the optical instrument 32 is located on the grasper86. The optical instrument can be used to position the tip of thegrasper 86 proximal to the implant 66. FIG. 25B shows a piercing element88 advanced through the cannula 30 to pierce the implant 66. The cannula30 can optionally comprise the piercing element 88 operable to piercethe implant 66 when the implant 66 is retracted against the cannula 30or the cannula is advanced against the implant.

After the implant 66 is punctured (at 96), it can be deflated in manyways. In some methods the implant 66 is allowed to deflate on its own.In other methods the implant 66 is deflated by forcing the implantagainst another structure such as the bladder wall or the cannula 30.FIG. 25C shows the partially deflated implant 66 being drawn into thecannula 30. This action can cause the implant 66 to deflate morequickly. FIG. 25D shows the deflated implant 66 withdrawn into thecannula 30. At this point, the removal device 150 and the implant 66 canbe removed from the urethra.

Example 3-Cage or Basket

FIG. 26A shows a cage-like device 98 in an expanded position afterexiting a delivery tube or catheter 30. The cage 98 can have two or more“legs” 91. The legs 91 can form the structure of the cage 98. Forexample, two legs 91 can form a loop sufficient to contain certainimplants. Alternately, Other embodiments include three legs 91 and stillothers contain four or more legs 91.

The cage 98 can have a first position configured to pass through thecatheter 30 and into the anatomical structure. The cage 98 can have asecond expanded position configured to obtain or catch the implant 66within the cage 98. In some embodiments, the legs 91 have hinges orjoints 97 that allow the cage to move from the first position to thesecond (FIG. 26B). In other embodiments, the legs are preformed or bentto be biased towards either the first or second position, or a positionin-between.

For example, in some embodiments the legs 91 are preformed to be biasedtowards an expanded position. The cage 98 and legs 91 can be compressedto fit inside the catheter 30 and can expand towards their biasedposition after exiting the catheter inside the anatomical structure.After obtaining the implant 66 within the cage 98, the cage 98 can bewithdrawn from the anatomical structure into the catheter 30. The act ofwithdrawing the cage 98 into the catheter 30 can cause the cage 98 tocollapse, or can compress the cage 98 and move it towards the firstposition.

In some embodiments, two of the three or more legs 91 can be oriented soas to create a window or door 95 on one side of the cage 98 that islarger than the space between the legs 91 on the other sides on the cage98. This larger window 95 can advantageously be used for capturing theimplant 66. FIG. 26B shows a cage 98 with three legs 91. Two of the legs91A are oriented roughly perpendicular to the other leg 91B, therebycreating the larger window or door 95 on one side of the cage 98 forcapturing the implant 66. When the implant is captured it can beretracted towards the catheter 30. In certain embodiments, retraction ofthe cage 98 into the catheter 30 collapses the cage 98 on the implant66. This can compress the implant, and in some instances pop or cause aleak or controlled expulsion of the implant's contents.

As mentioned above, the cage 98 can have hinges 97. The hinges 97 canallow the legs to move between different positions. A control 93 can beused to control the positions of the legs 91. For example, all of thelegs 91 can be connected and the control 93 can be connected to one ofthe legs 91 such that the position of the leg 91 connected to thecontrol determines the position of all of the legs 91.

The tip of the catheter can optionally carry an implant piercing orcompromising element 88 that pierces the implant 66 as it is retractedagainst the piercing element 88, as shown in FIG. 26C. The cage 98 canthen compress and deflate the implant 66. Alternatively, the tip of thecage 98 can include a needle at the distal end, pointed proximally tofacilitate puncturing and deflating the implant 66. The implant 66 canthen be retracted into the catheter 30 or the implant 66 can be releasedand allowed to pass naturally from the implantation site.

Example 4-Heating Element

Some embodiments provide a removal instrument 150 that uses electricalenergy to melt or burn the implant 66 to thereby deflate the implant.For example, one or more sides of a retrieval tool or grasper 86 can beadapted to transmit thermal energy including RF, electrical, laser, orhypothermal. The heated sides or sections are operable to melt theexterior of an implant 66 comprising a thermoplastic material. Accordingto some embodiments, this can allow the removal instrument 150 design tobe optimized for grasping ability while allowing easy penetration anddestruction of the balloon film with a heated surface. At the same time,according to these embodiments, the function of separately puncturingthe implant 66 does not need to be considered.

The heating element may be a resistor “R” as shown schematically inFIGS. 27A and 27B. The heating element can also comprise RF technology,as is used in electrosurgical units. The resistor “R” may take manyforms. The prong itself can form the resistor. The resistor “R” may beprinted on a miniature circuit board attached to the prong. Preferablythe flexible circuit board is less than 0.030″ wide. The flexiblecircuit board can be attached to a prong as a pad on the inside (balloonside) surface of the prong. The flexible circuit board can be a thinfilm deposited on the prong.

In another embodiment the prong or a part of the prong itself can bemade from nichrome resistance wire. In another embodiment, the resistercan be constructed from nichrome film attached to the inner side of oneor more prongs. Alternatively, the resistor can be made from constantan,inconel, TaN, Kanthal or any other appropriate resistance wire or alloy.In another embodiment, the prong can be made from resistance wire. Thegeometry of the prong can be designed to concentrate the current densityand therefore the heat at a particular location along the prong, such asthe apex.

One embodiment comprises a resistive element at the end of a cathetercarrying a forceps or grasper. Upon the application of current, theresistive element becomes hot, exceeding the melting point of theimplant material and breaking it open. In use, currents between 0.5 and10 amps can be used through resistances between 0.01 ohm and 1 K ohm.This can generate temperatures between 250 F and 500 F and can last forbetween 0.01 seconds and 3 seconds, preferable around 1 second to heatthe element sufficiently to melt the implant material. A current of 3.2amps through a resistance of 1.0 ohm has been shown to break apolyurethane balloon in approximately 1 second under water.

In some embodiments, a resistor “R” can be connected between two prongs,as shown in FIG. 27B. The prongs may or may not be insulated. Theresistor “R” can heat up while the prongs do not.

The circuit can be activated with a button on the handle of the deviceor can be automatically closed when the device contacts the implant 66.In some embodiments, contacting the implant causes the positive lead topress against the negative lead, closing the circuit. In anotherembodiment, the implant can be conductive. Contact between the implantsurface and the prong could close the circuit. Varying the resistance ofthe implant can control of the current flow and heating rate. When theprong is pulled away from the implant the circuit is opened and can coolimmediately.

In some embodiments, a short pulse may be created by mechanical orelectrical components to prevent continuous heating of the resister.Some form of capacitance may be used to create a high energy but shortduration electrical pulse.

The electrical energy for the circuit can come from an individualbattery or battery pack, possibly multiple 1.5V AA sized batteries or asingle 9V battery. Alternatively, an electrosurgical unit (such as thoseproduced by Valleylab of Boulder, Colo.) may be used to provide ACcurrent to the circuit.

In one embodiment, a capacitor can be used to store electrical energyfrom a power source with limited current producing capacity, such as abattery, which, when fired, gives a short burst of high current energyto rapidly heat the tip. In another embodiment, the catheter tip hastraces of deposited thin film metals which act as conductors to bringelectrical energy to a resistor at the tip. The circuit can be openedand closed in several ways including by button, lever, switch or otheractuator on the handle or catheter shaft, automatically by designing oneend of the circuit to be separated from and out of contact with theother end of the circuit coming into contact only when the tip ispressed against a surface.

In another embodiment, as shown in FIGS. 28A and 28B, the tip of acatheter 30 comprises a heating element 99. The tip 100 may be athermally resistant tip made from ceramic, metal, or high temperatureplastic onto which a thin film resistance metal is plated to create theheating element 99. The resistance film can be directly connected toconducting elements in the catheter shaft or connected to a conductingthin film 101 which is then attached to a conducting element in theshaft. Although bipolar electrocautery catheters are available, thisembodiment works differently as it does not require tissue (or otherconductive material) to close the circuit. In use, the tip 100 of thecatheter 30 becomes a heated element 99 capable of melting the surfaceof the implant 66 freeing up the inside of the catheter for the graspingtool. U.S. Pat. Nos. 4,532,924 and 6,986,767 are herein incorporated byreference and illustrate examples of bipolar electrocautery devices.

In another embodiment, a device similar to that shown in FIGS. 28A and28B, is made such that the positive and negative leads are situated oneover the other without touching, thus leaving the circuit open with nocurrent flow. When the tip 100 of the catheter 30, as shown in FIGS. 29Aand 29B, comes into contact with a surface the leads make contact,closing the circuit, and heating the resistor. When contact is released,the circuit opens, stopping current flow, and ending any heating of thetip. This reduces the possibility of overheating the tip or of heatingthe tip at an inopportune time. As shown in the detail view of FIG. 29B,at least one of the leads can be spring loaded 102 to allow the at leastone lead to move towards the other lead to close the circuit. Othermechanisms can also be used to move one lead towards the other.

FIG. 29C illustrates an alternative tip 100 with a resistor “R” formedon the tip.

Though various embodiments of delivery and retrieval devices have beendisclosed, it is to be understood that additional variations can also bemade and are envisioned. For example, the removal devices and methodscan be configured to prevent contact of the implant with the trigonearea of the bladder in similar ways to that described with respect tothe delivery devices and methods. As one example, the removal device canhave a lateral opening similar to the openings described in FIGS. 10A-E.

In accordance with another aspect of the disclosure, the delivery systemand the removal system of the attenuation device or accumulator are twoseparate instruments. In another embodiment, the delivery system and theremoval system are implemented using a single instrument. In yet anotherembodiment there is provided one instrument having different distal endsfor the delivery system and the removal system.

Therapeutic Benefits

Therapeutic Benefits, methods of improving the dynamic compliance of thebladder, methods of improving the contractility of the bladder: Based ondemonstrations by Solace, Inc. it is believed that the removal of highfrequency, repetitious insults to the bladder wall for a 5 day to 180day period of time increases the dynamic compliance of the bladder andreduces symptoms of incontinence by: precluding/reducing the stretch ofelastin fibers; reducing of the conversion of elastin fibers intocollagen; allowing the “stretched” muscles of the bladder wall toshorten, thereby improving compliance and bladder wall contractility;removing pressures exerted on the pelvic floor and connective tissues,allowing retraining and healing, increasing urethral resistance; placingthe attenuation device in the bladder provides passive resistance to thebladder neck and bladder wall, allowing the muscles to strengthen. Theseand other therapeutic benefits could last up to about 30 days to aboutone year. An additional benefit of attenuation and/or improving bladdercompliance includes improved flow during voiding (i.e. method ofimproving flow during voiding by “smoothing” the pressure within thebladder). Abdominal straining, resulting in a raised abdominal pressureP_(abd) and, therefore, an increased intravesical pressure is not oftenemployed in normal voiding, nor is it usually as efficient as detrusorcontraction in producing voiding. If, however, the detrusor contractionis weak or absent abdominal straining may be the only available way ofvoiding and may then become of primary importance.

Another benefit of attenuation and/or improving bladder complianceincludes improved urethral closure pressures. Changes in abdominalpressure affect not only the intravesical pressure but also the urethra,proximally by direct mechanical action. The result is that when theabdominal pressure rises, as during straining or a cough, the urethralpressure discussed above also rises. The maximum urethral closurepressure therefore does not diminish, and may even increase. Thisrepresents a natural defense against leakage during stress. This processis enhanced by the attenuation of intravesical pressures within thebladder, with full exposure of the urethra to increased abdominalpressures.

Another benefit of attenuation and/or improving bladder complianceincludes improving the symptoms of benign prostatic hypertrophy (“BPH”).As the prostate enlarges, flow rates are reduced and residual volumesincrease. The symptoms of low flow are increased as the increasedintravesical pressure causes a decrease in the compliance of the bladderwall, bladder muscles elongate, elastin converts to collagen in the mostsevere cases), making it even more difficult for the bladder to “push”the urine through the restricted opening of the prostate. As thiscascade continues, the symptoms of benign prostate hyperplasia increase.Placement of an attenuation device in the bladder reduces symptoms ofBPH by improving flow, increasing the compliance of the bladder wall,removing high pressure insults to the bladder wall, and allowing thebladder wall muscles to shorten, all permitting the bladder to moreeffectively “push” the urine through the urethra and prostate. In oneembodiment, the attenuation device in the bladder reduces the symptom ofBPH by attenuating increases in pressure within the bladder byreversibly reducing its volume in response to the pressure increases.For example, in one embodiment, the attenuation device reduces itsvolume by at least 5%. In another embodiment, the attenuation devicereduces its volume by at least 10%. In yet another embodiment, theattenuation device reduces its volume by at least 25%.

FIGS. 30A-D illustrate attenuation (i.e. pressure reduction) withvarious attenuation device air volumes. The data for these graphs weregenerated using a bench top bladder simulation program. Here, themaximum spike pressure is 2.0 psi. The spike event duration isapproximately 40 ms, which is approximately equivalent to the durationof a coughing or sneezing event. With reference to FIG. 30A, a test wasconducted with a 250 ml rigid plastic container filled with syntheticurine or water. A regulated pressure of 2.0 psi was introduced into thecontainer via a controlled solenoid valve. A pressure transducerdetected the pressure rise. Here, the pressure rise time (Tr) of thecontainer pressure 422 to reach 2.0 psi was approximately 40 msec. Withreference to FIG. 30B, a similar test was conducted on a 250 ml rigidplastic container. Here, an attenuation device filled with 15 ml of airwas placed inside the container filled with synthetic urine. Here, theTr of the container pressure 424 to reach 2.0 psi was approximately 195msec. Thus, the attenuation device slowed the rise time by 4.8×. Duringthe spike event (i.e. when time equaled 40 msec), the pressure insidethe container reached 0.7 psi (vs. 2 psi), resulting in a 65% reductionof pressure vs. baseline. With reference to FIG. 30C, a similar test wasconducted; the only difference being that the attenuation device wasfilled with 25 ml of air. Here, the Tr of the container pressure 426 toreach 2.0 psi was approximately 290 msec. Thus, the attenuation deviceslowed the rise time by 7.25×. During the spike event (i.e. when timeequaled 40 msec), the pressure inside the container reached 0.5 psi (vs.2 psi), resulting in a 75% reduction of pressure vs. baseline. Withreference to FIG. 30D, a similar test was conducted; the only differencebeing that the attenuation device was filled with 30 ml of air. Here,the Tr of the container pressure 428 to reach 2.0 psi was approximately340 msec. Thus, the attenuation device slowed the rise time by 8.5×.During the spike event (i.e. when time equaled 40 ms), the pressureinside the container reached 0.4 psi (vs. 2 psi), resulting in an 80%reduction of pressure vs. baseline.

FIGS. 31A-D show pressure vs. time curves generated by a bench topbladder simulator. FIG. 31A shows the baseline pressure-time curvewithout an attenuation device. FIG. 31B shows the pressure-time curvewith an attenuation device having a 15 cc air volume. FIG. 31C shows thepressure-time curve with an attenuation device having a 25 cc airvolume. FIG. 31D shows the pressure-time curve with an attenuationdevice having a 30 cc air volume.

Another benefit of some of the devices discussed herein is the abilityto treat and/or prevent stress urinary incontinence. A method ofpreventing stress urinary incontinence can include providing apressurized implant operable to reversibly occupy intravesical space inresponse to a pressure increase event within a bladder said responseoperable to impede the rate of an intravesical pressure increase eventduring an initial period. The initial period can be around 0milliseconds to 1 second from the event. This can beneficially allowtime for neurological signaling of a guarding reflex to increase theoutlet resistance of an external urinary sphincter sufficient to preventleakage of urine through said sphincter after said initial period. Theselected treatment period can beneficially facilitate rehabilitation ofa neuromuscular system of the bladder and restoration of continence.

Selectably Pressurized Implants

All liquids (and for that matter solids) will evaporate at a giventemperature until they saturate the space above the liquid with theirvapor. The pressure exerted by that saturated vapor is the vaporpressure. The vapor pressure goes up with temperature and when a liquidis heated until its vapor pressure is above one atmosphere, it boilswhile trying to maintain the space above it at its vapor pressure, nowmore than one atmosphere. Likewise if the vapor of a liquid isconcentrated (e.g. compressed) to be present at a partial pressure(concentration) above its vapor pressure, it condenses. Some liquidshave very low vapor pressures (e.g. cooking oil, high molecular weightPFCs) and some have high vapor pressures (e.g. alcohol, gasoline, lowermolecular weight PFCs). Within this document the abbreviation, PFC, isused for perfluorocarbon.

Partial pressure is both a measure of pressure (force/area) and a unitof gas concentration (at constant temperature, proportional tomoles/volume). A “p” placed in front of the chemical symbol of a gasgenerally denotes it as the partial pressure of that gas, e.g. pCO₂. Thetotal of all partial pressures inside a container is the gas pressuremeasured inside that container. Diffusion is controlled by thedifference in concentration across a boundary or membrane and thus forgases the rate is proportional to the difference in partial pressures ofthe gas on both sides of a membrane.

Gas tension is a measure of the amount of a gas dissolved in a liquid(e.g. O₂ or CO₂ in blood, urine). It is a preferred measurement for theliquid systems described here. Gas tension is defined as the partialpressure of a gas that would equilibrate with the liquid sample causingit to contain the same quantity (g/ml or moles/liter) of that gas as isin the test sample. It is expressed as a partial pressure with units ofmm Hg, torr, or cm H₂O.

Many of the devices herein rely on compliance to attenuate or bufferpressure spikes, such as in the bladder. Compliance is the change involume (V) of a device per unit change in applied pressure (P) on thedevice (dV/dP). This is the slope at any point in a plot of volume (V)of the device vs. pressure (P) applied to the device. For example,compliance is often calculated from V vs. P curves of the lung toindicate the effort needed to breathe. In our case it is a measure ofhow capable a device is of dampening a pressure spike. High compliancemeans a large device volume reduction to relieve a given pressure spike.Since the V vs. P curve is often non-linear, the slope,dV/dP=compliance, is not constant throughout the working region of adevice. Internal gas pressures, geometry of the device, volume of thedevice and elasticity of the skin of the device can be chosen tomaximize compliance under the conditions expected for each application.

Tables and charts are readily available which show the vapor pressure ofa given PFC as a function of temperature and can be useful in designinga device with certain pressure properties, as will be shown below.

For liquids, the amount of dissolved gas is stated as a gas tension.This is the equilibrated partial pressure of the gas that results in theamount of dissolved gas. Since this is the liquid concentration that isrelevant for diffusion across biological membranes, it is commonly usedin medicine for gases in the blood e.g. pO₂ or pCO₂ and has units ofpressure, e.g. mm Hg, or cm H₂O. Gas tensions are actually a measure ofsaturation level rather than true concentrations. Thus, a sample ofblood with a N₂ tension of 593 mm Hg or O₂ tension of 160 mm Hg would besaturated with those gases when exposed to a gas mixture containingpartial pressures of 593 mm Hg of N₂ or 160 mm Hg of O₂. This isregardless of how many moles or milligrams per ml were dissolved in thesample. Unlike gaseous systems where compression of the system elevatesthe gaseous partial pressures in the system, gas tensions of gasmolecules dissolved in an incompressible liquid are not affected byhydrostatic pressures.

Another factor to consider is the fact that a vessel/balloon containinga gas and/or a liquid could be constructed of an elastic material. Asthe pressure of gas inside the balloon increases relative to thepressure outside the vessel, the vessel may seek to expand to neutralizethe difference in pressure between inside and outside the vessel. As thevessel expands it will stretch and exert a force which countermands theforce of the gas pressure within. This is sometimes known as skintension causing skin pressure. Thus, an equilibrium state could existwhere the pressure outside such an elastic vessel is 760 mm Hg, thepressure inside the vessel is 780 mm Hg, and the skin tension of thevessel exerts a force on the gas within it that is equal and opposite tothe expansionary force of the extra 20 mm Hg within the vessel.

It is important to consider the gases and the concentrations of thosegases which may be found within the body when placing an implanttherein. Generally, there is a close relation to the gases found in theambient atmosphere outside the body, and those within. In normal air,the largest component is nitrogen. The components of a gas are, in factreferred to according to their partial pressures. That is, when it issaid that air is 78% nitrogen, it means that this is the percentage ofthe total gas pressure due to nitrogen. The second most common componentis oxygen, whose partial pressure contributes 21% of total atmosphericpressure. Other gases make up the remaining 1% (e.g. CO₂ is 0.04% andthus may be neglected in most calculations discussed herein) of thetotal pressure. Also, the body does not metabolize nitrogen, and it ispresent within the body's fluids, and its partial pressure contributionis related to its contribution outside the body, limited by itssolubility in the respective fluids. Thus, if the ambient pressure is760 mm Hg, then the total pressure is 760 mm Hg, the partial pressure ofnitrogen is 593 mm Hg or 78%. The partial pressure of oxygen, expressedas pO₂, is 160 mm Hg, or 21%. The partial pressure of the remaininggases would be about 8 mm Hg, or about 1%.

The nitrogen concentration in blood is related to nitrogen's solubilityin blood but, since it is not metabolized, its gas tension isessentially equal to the nitrogen partial pressure in air. The oxygenconcentration in blood is more complex, since oxygen is actively boundto hemoglobin in the blood—boosting blood's capability to carry oxygen.Also, unlike nitrogen, oxygen is metabolized in the body, so itsconcentration can vary significantly within the body. The amount ofoxygen present in blood varies and is reported as “oxygen saturation,”or the % of the maximum oxygen that blood can carry or the oxygentension pO₂. For a healthy person, this is typically in the range of 95to 98%. Venous blood is typically in the range of 60 to 80%. Whenconsidering the diffusion of oxygen across membranes the preferredmeasurement is the oxygen tension or pO₂. Oxygen concentration in fluidssuch as cerebrospinal fluid, vitreous humor and bladder urine alsovaries.

In the article “Noninvasive Oxygen Partial Pressure Measurement of HumanBody Fluids in Vivo Using Nuclear Magnetic Imaging” by Zaharchuk et al.(Acad. Radiol. 2006; 13:1016-1024), a table of gas tensions of oxygen invarious body fluids is detailed. Information from that article issummarized in Table 1, below. The authors, Zaharchuk et al., attemptedto measure partial pressure of gases in the body using MRI. In an effortto verify their measurements they performed a literature review to seewhat other researchers had estimated the partial pressures to be.

In Table 1, the oxygen partial pressure for particular bodily fluids isgiven. The middle column is Zaharchuk's measurement and the right columnis what they found by studying the literature. Also, one should notethat the partial pressure of oxygen in the atmosphere is 160 mm Hg andthus consequently fully air equilibrated fluids, if there were noconsumption, would have oxygen tensions of 160 mm Hg.

TABLE 1 Body Fluids and Oxygen Partial Pressure Values Actual pO₂measured Literature Review by Zaharchuk “best estimate” Body Fluid etal. (mmHg) range of pO₂ (mmHg) Cerebrospinal fluid in 52 +/− 14 30-74Lateral ventricles Cerebrospinal fluid in 62 +/− 29 31-74 Cisterna magnaCerebrospinal fluid in 138 +/− 46  Not Found in the cortical sulcalLiterature Cerebrospinal fluid in 69 +/− 22 40-57 lumbar subarachnoidVitreous Humor 63 +/− 34  9-20 Bladder Urine 63 +/− 16 25-80

Pressure within the abdomen and within the bladder is typically measuredin units of “centimeters of water” or cm H₂O, where 1.0 mm Hgcorresponds to 1.33 cm H₂O. So, for example, the partial pressure ofoxygen in atmospheric air is about 212 cm H₂O, and the partial pressureof oxygen in bladder urine is approximately 84 cm H₂O. Hence, there is apartial pressure “deficit” of oxygen in bladder urine corresponding toapproximately 129 cm H₂O.

Provided herein are improved pressurizable, compressible and/orexpandable devices for attenuating pressure waves or spikes in the bodyand for preventing or relieving various pathological conditions andimproving surgical outcomes.

Several of the therapeutic devices herein are comprised of implantableballoons, vessels, enclosures, envelopes, pistons or hydraulic devicesthat contain gas or gas/liquid mixtures. Such devices can define a rangeof permeability. Examples of such devices can be found in U.S. Pat. No.7,347,532 and US Publication No. 2007-0156167 herein incorporated byreference. Various embodiments herein provide for rapid, delayed orcontrolled in situ inflation or deflation. In other embodiments thedevices may further be comprised of relatively soft, distensible, thin,and consequently gas permeable membranes. Over time these devices willdeflate and become ineffective or fail unless fitted with a “gasgenerator” of a selected high vapor pressure media. Certain othermethods and devices provided herein include the maintenance of inflationfor a selected period of time.

In one embodiment, an implant 66, such as a silicone balloon device, isplaced in the bladder to attenuate pressure spikes that would otherwisecause urinary incontinence. As shown in FIGS. 32A and B, pressure “P” onthe bladder, for example from physical activity can cause urine leakage104 in those who suffer from urinary incontinence. The implant 66 canabsorb the pressure in the bladder so that there is no urine leakage.

The pressure within the bladder is typically a little bit higher thanatmospheric pressure, since it typically contains urine which displacesthe bladder's muscular walls. The walls of the bladder, through theirmuscle tone and mass, exert force on the urine inside, resulting intypical pressures that can be around 15 cm H₂O above atmospheric in somepatients. For the sake of simplifying discussion in this document, wewill simply use this number as an approximation of average bladderpressure. If the silicone balloon is under-filled with air such thatthere is no skin pressure to consider, then there will be a situationimmediately before the balloon is placed in the bladder where thepressure within the bladder is atmospheric plus 15 cm H₂O, and thepressure within the balloon is atmospheric pressure. When the balloon isplaced within the bladder, the balloon will instantaneously compress, sothat its contents are at the same total pressure as the hydraulicpressure with which the urine in the bladder is pressing on the balloon.That is, the now slightly compressed gas will press outwards on thewalls of the balloon with the same force that the liquid in the bladderwill push inwards. This “force equilibrium” of exactly equal andopposite forces exerted from within the balloon outwards, and outsidethe balloon inwards is one equilibrium that should be considered in thisexample.

In the force equilibrium, the liquid or hydraulic pressure within thebladder pushes on the balloon, and the now slightly compressed gaswithin the balloon pushes outwards on the liquid. The inwardly pushingforces should balance with the outwardly pushing forces or the balloonwill either burst or collapse.

The second equilibrium to be considered is partial pressure equilibrium.The partial pressures of the individual gas constituents within theballoon will seek to equilibrate with the gas tensions of the dissolvedgas in the liquid outside the balloon.

In this example, first assume that initially, before the balloon wasinserted, that the proportions of gas in atmospheric air were in theballoon, and that the same proportions of dissolved gas existed in theurine. The balloon was compressed slightly when it was inserted, so allof the partial pressures of the gas constituents increased by an amountproportional to the decrease in volume due to the compression. Thisresults in a situation where there will be higher partial pressures ofthe individual gas components inside the balloon versus the gas tensionsof the same gases outside the balloon. This will result in diffusion ofthese gases out of the balloon into the urine. As the gases leave theballoon, the balloon will shrink to maintain the force balance. In thisexample, this net out-of-the-balloon gas diffusion will continue untilthe balloon is completely empty. The rate of deflation will be afunction of the permeability of the membrane to the gases held withinand the difference between the hydrostatic pressure in the bladder andthe total gas tension of gases dissolved in the urine.

In one aspect of this disclosure an important step is the addition ofPFC to the contents of the balloon. Since some selected or preferredPFCs have high vapor pressures, the partial pressure of the PFC will addto the existing partial pressures of the other gases to increase theoverall gas pressure in the device. A small amount of liquid PFC withinthe balloon serves as a reservoir or generator and will offset lossesdue to slow diffusion and maintain a constant PFC partial pressure.

FIG. 33 illustrates this generator system. The volume of the gas (V_(G))remains constant as long as there is a volume of liquid PFC (V_(L))within the balloon. The liquid PFC recharges the volume of gas throughvaporization. Even after all the liquid has vaporized, the volume of gasremains at a constant volume until a time T₂ where the gas tensionbegins to be insufficient to maintain the volume V_(G).

The total pressure in the balloon will be the sum of the partialpressures of its components, as described by Dalton's law. Due to the“force” equilibrium, in this case, the balloon will now expand orcontract until the total pressure within the balloon balances the forcesdue to the hydraulic pressure outside the balloon. If the pressureexternal to the balloon is 15 cm H₂O higher than atmospheric pressureand the vapor pressure of the PFC is 120 cm H₂O, assuming the PFCachieves its vapor pressure equilibrium instantaneously, it would seemthat the balloon would have a pressure of 105 cm H₂O higher than outsidethe balloon, which is impossible. What will actually occur is that theballoon will expand by a volume proportional to this pressure deficit tosatisfy the force equilibrium. The now expanded balloon will now havepartial pressure deficits for its gas components. This will result inthe inward diffusion of gas to satisfy the gas partial pressureequilibrium. As the gas comes into the balloon, the balloon will expandslightly to maintain the force equilibrium, until a fairly staticsituation is achieved. This situation will be characterized by a stablevolume balloon, containing liquid and gas PFC, and gas components whosepartial pressures match the respective gas tensions of the gasesdissolved in the urine. This stable balloon volume will occur if thedifference between the total gas tension of the urine and the absolutehydrostatic pressure in the bladder approximately equals the PFC vaporpressure.

This example neglected the effect of the skin tension exerted by theballoon as it expanded. This would simply result in one additionaladditive factor for the force balance equation. In this case, theballoon's expansion would be limited by the inward force exerted by thewall of the balloon as it stretches.

The stable size of the balloon depends on the maintenance of a supply ofliquid PFC inside the balloon, the balance of force as regulated byballoon size, and the balance of partial pressures. If any of these keyfactors moves out of balance the balloon will either grow or shrink.

Selection and Determination of the Vapor Pressure or Partial PressurePFC Element

In a simplified embodiment involving an air-filled balloon placed intothe bladder or other liquid filled bodily organ one will note that thedevice will float in the bladder and rest near the top of the bladder.It will not deflate; therefore there is equilibrium between the airinside the balloon and the liquid pressing upon it. The gas moleculesinside the balloon provide an internal force (F_(int)) that pressesoutwards, and the hydraulic pressure of the urine provides an externalforce (F_(ext)) that presses inward on the balloon. For the balloon toexist, the forces should be in balance as illustrated here, that isF_(int)=F_(ext). The internal force is created by the pressure of thegas inside the balloon.

In this example, the gas inside the balloon was normal atmospheric air,at sea level, when it was inserted. So its total pressure beforeinsertion was approximately 760 mm Hg which is approximately equal to1000 cm H₂O. This total pressure of 1000 cm H₂O is, as described byDalton's law, equal to the sum of the partial pressures of its gascomponents. Normal atmospheric air is comprised of approximately 78%nitrogen, 21% oxygen, and 1% other gases. Since the total pressure is1000 cm H₂O, we can surmise that the partial pressure of nitrogen orP_(N2) is equal to 780 cm H₂O, the partial pressure of oxygen or P_(O2)is roughly 210 cm H₂O, and the partial pressure of other gases or P_(OG)is 10 cm H₂O. The partial pressures and total pressure of the balloonoutside the bladder are shown in Table 2.

TABLE 2 Internal Balloon Pressure When Outside the Bladder P_(N2) = 780cm H₂O P_(O2) = 210 cm H₂O + P_(OG) =  10 cm H₂O Balloon total pressure= 1000 cm H₂O 

As soon as the balloon is inserted into a urine filled bladder or organ,it will be subjected to hydraulic pressure due to the muscle tone of theabdomen and bladder pressing on the urine within. This is a frequentlymeasured physiological parameter, and 15 cm H₂O is a typical value, sowe will use this in our example. Now, the patient into whom the balloonhas been inserted is residing at sea level, so this “inside the bladder”(or intravesical) pressure is equal to the sum of atmospheric pressureplus the 15 cm H₂O, or 1015 cm H₂O. This means that in order to satisfythe force equilibrium, the total pressure inside the balloon changes sothat it equals 1015 cm H₂O also. It does this by compressing and gettingsmaller. The balloon will instantaneously compress as it is insertedinto the bladder. According to Boyle's law, the pressure and volume of agas are directly proportional according to the relationship: P₁V₁=P₂V₂.This means that in order for the gases' volume to decrease, its pressureincreases, in this case by 15 cm H₂O or by 1.5%.

The total pressure of the gas inside the balloon has now changed, due tothe compression, but the molar quantities and proportions of the gaseswithin has not changed. Table 3 shows the partial pressures and totalpressure of the balloon inside the bladder are (with rounding).

TABLE 3 Internal Balloon Pressure When Inside the Bladder P_(N2) = 780 +1.5% = 792 cm H₂O P_(O2) = 210 + 1.5% = 213 cm H₂O + P_(OG) =  10 + 1.5%=  10 cm H₂O Balloon total pressure = 1015 cm H₂O 

In this example, gas diffusion equilibrium should also be considered.Urine in the body, like other body fluids, contains dissolved gas. Theamount of gas dissolved in these fluids is governed by the gases'solubility in the fluid, and whether or not it reacts chemically orbiologically with the fluid. For example, blood can contain a muchhigher percentage of oxygen than water, due to the fact that the oxygenis bound to the hemoglobin in red blood cells. The gas tensions of gasesin urine will be different than the partial pressures of gases found inatmospheric air (most likely lower). The gas tensions will also not begoverned by the hydraulic pressure of the fluid, since these fluids are,relative to gas, incompressible and hydraulic pressure does not affecttheir solubility.

In an embodiment wherein the balloon is constructed of a material thatis permeable to gas, the gas will seek to diffuse from the high partialpressures in the balloon into the liquid where the gas tensions arelower. For example, consider the fact that the partial pressure ofoxygen in bladder urine could be around 84 cm H₂O (as describedpreviously) and in this example, the partial pressure of oxygen is 213cm H₂O in the balloon. This gradient will result in oxygen exiting theballoon at a rate determined by the gas permeability of the wall of theballoon. As the oxygen exits, the balloon will shrink to maintain theforce equilibrium. This exiting of oxygen, and balloon shrinkage will beechoed by nitrogen and the other gases present, although at varyingrates. The end result will be complete deflation of the balloon overtime.

A means to maintain balloon inflation, as described above, is to providea supply of liquid PFC inside the balloon. The liquid PFC will rapidlyvaporize, and provide a supply of PFC gas whose partial pressure is“locked” at the vapor pressure of the PFC. This PFC will not diffuse outof the balloon as it is not soluble in water or urine. Let's consider aballoon containing a PFC whose partial pressure is 120 cm H₂O, plusnormal air, inserted into the bladder as before. Table 4 shows thepartial pressures, if the balloon was hypothetically filled outside thebladder at atmospheric pressure, before the PFC has a chance tovaporize.

TABLE 4 Internal Balloon Pressure Before Vaporization P_(N2) = 780 cmH₂O P_(O2) = 210 cm H₂O P_(OG) =  10 cm H₂O + P_(PFC) =  0 cm H₂OBalloon total pressure = 1000 cm H₂O 

In this example, outside the bladder situation, as the PFC vaporizes,the balloon will expand to maintain the force equilibrium. The gasquantities and proportions other than the PFC will remain constant, sothey are, in effect, diluted by the PFC whose partial pressure will befixed at its vapor pressure of 120 cm H₂O. Thus, moments later, thepartial pressures in the now expanded balloon will be as shown in Table5. The balloon will have expanded 12%, the partial pressures of theconstituent gases other than PFC will maintain their proportions sincethe moles of gas are the same; however they will reduce proportionallyas shown:

TABLE 5 Internal Balloon Pressure After Vaporization P_(N2) = 686 cm H₂OP_(O2) = 185 cm H₂O P_(OG) =  9 cm H₂O + P_(PFC) = 120 cm H₂O Balloontotal pressure = 1000 cm H₂O 

If this balloon is placed into the bladder, then the bladder pressure,15 cm H₂O, should equilibrate to a new total pressure of 1015 cm H₂O asbefore. The balloon will shrink by 1.5% and the new partial pressuresare shown approximately in Table 6.

TABLE 6 Internal Balloon Pressure After Vaporization When Inside theBladder P_(N2) = 697 cm H₂O P_(O2) = 189 cm H₂O P_(OG) =  9 cm H₂O +P_(PFC) = 120 cm H₂O Balloon total pressure = 1015 cm H₂O 

If the gas tension of dissolved gas in the urine is lower than the newpartial pressures in the balloon, gas will be driven out of the balloonat a rate which is regulated by the gas permeability of the balloon, andthe balloon will shrink. If the partial pressure of the dissolved gas inthe urine is higher than these new partial pressures, then gas will bedrawn into the balloon at a rate which is regulated by the gaspermeability of the balloon, and the balloon will grow. However, thepartial pressure of the PFC will remain fixed. Note that for simplicity,this example excluded the impact of the skin tension of the balloon. Thenext example will consider skin tension.

The partial pressure of the PFC can be selected by tuning its vaporpressure. In order to maintain a balloon whose volume is stable, the PFCshould be selected so that a diffusion balance is maintained. Theformula can be derived as follows. First, the pressure inside theballoon equals the pressure outside the balloon, or else the balloonwill collapse or burst.

P _(Inside Balloon) =P _(Bladder-avg) +P _(Skin-tension)  (1)

As discussed infra, P_(Inside Balloon) (the pressure inside the balloon)is equal to the sum of the partial pressures of the gases within theballoon. As shown here, it is also equal to the hydraulic pressurepushing upon it plus the pressure due to the balloon skin. The term,P_(Bladder-avg), comprises the hydraulic pressure pushing upon theballoon due to abdominal pressure, bladder muscle tension and otherfactors. The skin pressure, P_(Skin-tension), is the inward forceexerted by the stretching material of a balloon's walls, or in othercases, simply the weight exerted on the gas within by a flaccid underinflated balloon. This equation is simply another version of the “forceequilibrium” equation described earlier.

At the same time, recall that the total pressure within the balloon isequal to the sum of the partial pressures of the gases it contains:

Note: All pressures below are absolute pressures

P _(Inside Balloon) =P _(N2-balloon) +P _(O2-balloon) +P_(other gases-balloon) +P _(PFC)  (2)

Since the partial pressure of the other gases is only 1% of the sum ofall the non PFC gases, this can be approximated as being zero, so:

P _(Inside Balloon) =P _(N2-balloon) +P _(O2-balloon) +P _(PFC)  (3)

Equation (1) from the force equilibrium was as follows:

P _(Inside Balloon) =P _(Bladder-avg) +P _(Skin-tension)  (1)

Therefore combining equations (1) and (3) gives:

P _(Bladder-avg) +P _(Skin-tension) =P _(N2-balloon) +P _(O2-balloon) +P_(PFC)  (4)

Over time, gas diffusion will occur, and P_(N2-balloon) andP_(O2-balloon) will equilibrate to values that approximate the partialpressures of oxygen and nitrogen dissolved in the urine (their gastensions). Therefore:

P _(N2-balloon) +P _(O2-balloon) =P _(Dissolved gas)  (6)

And by combing (4) and (6) we get:

P _(Bladder-avg) +P _(Skin-tension) =P _(Dissolved gas) +P _(PFC)  (7)

Or

P _(PFC) =P _(Bladder-avg) +P _(Skin-tension) −P _(Dissolved gas)  (8)

Where:

P_(PFC)=The desired vapor pressure of the PFC.

P_(Bladder-avg)=The average bladder pressure over time (i.e. course of aday) or more generally, the anatomical environment/hydrostatic average.

P_(dissolved-gases)=The total gas tension of bladder urine.

P_(skin tension)=The inward force exerted by the skin of the balloon.

More generally, the equation for selecting a PFC suitable formaintaining a pressurized device according to one or more aspects of thedisclosure in a given anatomical environment is:

P _(PFC) =P _(anatomical environment/hydrostatic-avg) +P _(Skin-tension)−P _(Dissolved gas)  (9)

In another embodiment the selection for the high vapor pressure elementcan be described as:

atmospheric pressure+Ppfc=external pressure or loads on implant  (10)

Where the external loads include: tension generated by skin of theballoon, normal somatic pressure during fill and void of organ (ifapplicable), transient somatic pressure, e.g. abdominal, patientgenerated Valsalva, bodily weight on organ e.g. abdominal weight onbladder or on bladder wall/balloon when the bladder is empty,differential between gas tensions in body fluid and partial pressureswithin balloon.

Having shown how to determine an appropriate vapor pressure for the PFCelement, one can now select an appropriate mixture of PFCs toapproximate this value. The P_(PFC) can be selected by mixing PFCs ofdifferent vapor pressures, and calculating the composite vapor pressurebased on the proportions of the moles of the individual PFCs.

One consideration is the average pressure within the desired area of thebody (P_(anatomical environment/hydrostatic-avg)). In the example of adevice implanted in the bladder, the average pressure within the area ofthe body would be a time average of the pressure in the bladder(P_(Bladder-avg)). This would encompass the average of: the low pressureof slowly filling bladder; pressure spikes from events such as laughs,coughs or sneezes; higher pressures achieved during micturition, orduring Valsalva. Other hollow organs and tissue sites would similarlyvary in pressure ranges, from which an average value could becalculated.

Another consideration is the total gas tension of the bodily fluid inthe particular area of the body (P_(Dissolved gas)) to be treated. Thisincludes all the dissolved gases in the bodily fluid such as oxygen,nitrogen, carbon dioxide, or other gases. In the bladder, the bodilyfluid is urine. The total gas tension in urine can vary based on thepatient's diet, presence of substances in the urine that bind oxygen orother gases, or the gases that the patient is inhaling. For example, apatient breathing pure oxygen would have a higher oxygen gas tension. Itis also worth noting that gas tension will almost always be less thanthe hydrostatic, anatomical pressure, or bladder/organ/implantation sitepressure. Also note that the driving force for deflation is that theconcentration of gases inside the device is higher than the total gastension outside the device.

Several of these parameters will vary from patient to patient. Forexample, average bladder pressure in men is generally higher than thatof women. Average bladder pressure can vary from person to person withina gender based on how full each individual lets their bladder get beforevoiding. Also, average bladder pressure may vary due to pathology, forexample, due to a condition known as detrusor instability which causesundesired contractions of the bladder's muscular walls. Bladder pressurecan also vary due to physical activity. One would expect that theaverage bladder pressure of a weight lifter would be higher during aweight lifting competition than it is for a sedentary individual. Asmentioned above, the bladder gas tensions can vary based on diet, lungfunction, metabolic rate and other factors.

An additional consideration is the skin tension of the balloon. The skintension of the balloon can vary based on many factors, including thematerial of the balloon, the thickness of the material, and its means ofconstruction. It can also vary based on how “stretched” it is. Forexample, a balloon that has a volume of 3 ml when empty and is filledwith 15 ml will be much more stretched than the same balloon filled to 5ml.

It is conceivable that a balloon that has a stable volume over timecould be created by measuring each of the above parameters and selectingthe PFC based on that. Also, an individual could be “titrated” so thatvarious PFCs are tried and one that is stable over time is selected. Acombination of the two methods could be used as well—for example, grossmeasurement of physical parameters followed by “trying” PFCs ofdifferent partial pressures.

Various means could be used to achieve this measurement and/ortitration. For example, a pressure sensor that resides in the bladderand either transmits data out of the bladder telemetrically, or storesit for later retrieval, could be used to determine average bladderpressure. Pressure information of other hollow organs such as the eye,heart, cranium, lungs, stomach, liver, gal bladder etc. or bodily sitescould similarly be obtained. Sensors, such as those used for blood gasmeasurement could be used to measure the total gas tension of urine inthe bladder and the individual tensions of the constituent gases.Finally, balloons can be selected or filled in order to achieve adesired skin tension. Test device involving balloons with strain gaugesand pressure gauges to record or transmit data for short time could alsobe used to determine pressures and skin tension values.

Two examples of how the gas pressures in urine could be measured includethe use of a blood gas analyzer, such as those available from RadiometerAmerica Inc. or the MRI approach described by Zaharchuk et al.,referenced above.

A blood gas analyzer can be used to sample gases in the urine. Apatient's bladder would be allowed to fill normally. A catheter or tubewould be inserted into the patient's bladder. Urine would be extractedinto a syringe or vial. The vial would be inserted into the machine, andstandard readouts can be obtained. P0₂ (partial pressure of oxygen inthe sample) is an example.

The blood gas analyzer runs the risk of inaccuracies related to howquickly the measurement is performed. The sample can become contaminatedin the time between taking the sample and sending to the lab. Also, themeasurement may not be as accurate as needed since there is measurementerror in the machine. A difference of 10 cm H₂O can be enough to makethe difference with regard to a balloon inflating or deflating thus,these inaccuracies can be make the error too great to be useful.

Concerning MRIs, MRI machines are big, and expensive. Thus, it is notpractical to place every patient inside an MRI machine. Furthermore theaccuracy of the method ranges from +/−14 mm Hg to +/−46 mm Hg. 14 mm Hgcorresponds to +/−18.6 cm H₂O, too broad a range for most applicationsdescribed herein.

A preferred method is to “titrate” the PFC. First, based on theinformation described herein the Physician can estimate the relative gaspartial pressures in urine and the needed partial pressure of the PFC.For example, the estimate can be in the range of 100 to 130 cm H₂O. Aclinical study can be performed in which a series of patients arestudied using balloons containing PFC with a partial pressure of 110 cmH₂O. The state of these patient's balloons upon removal would bemonitored carefully. One possible result is that on average the balloonscould be decreasing slightly in size over a 3 month period. Continuingthe example, another series of patients could be studied using a PFCwith a vapor pressure of 120 cm H₂O. Upon examining their balloons after3 months, one possible result is that their balloons could be growingslightly in size over 3 months. This result would tell us that the idealvapor pressure would be in between 110 and 120 cm H₂O. The next stepwould be to try a series of patients with a vapor pressure of 115, andso on.

One reason that the titration method is preferred is that the desiredoutcome is the best partial pressure on average over time. The partialpressure of oxygen in urine, for example, will change over the course ofthe day. It is likely to be different during sleeping and waking hours.It can also be affected by diet, for example, eating foods rich inascorbic acid (vitamin C) can affect oxygen partial pressure. Thetitration method yields the value that is optimum for the long termsuccessful inflation of the balloon. Other methods that provide aninstantaneous measurement (such as blood gas monitors or MRI) would notprovide this benefit. It would be impractical to make such measurementsmany times over the course of a day, days, or even weeks or months.

Setting the Vapor Pressure of the Selected PFC Element

The PFC vapor pressure of the PFC element or additive can be set bychoosing the molecular weight/number of carbons and isomer form of thePFC (rings, branched, linear) or using hetero-atoms such as Br or H.These pure compounds will have a constant vapor pressure throughout thelife of the device as it very slowly looses PFC through the aqueousfluid surrounding the device.

Intermediate vapor pressures can also be produced by using mixtures ofPFCs, though these mixtures will change component ratios after initialvaporization and slowly through the life of the device. If mixtures areused, an excess quantity of PFC should be put in the device to minimizethe vapor pressure changes (unless we want the vapor pressure and thusinflation pressure to slowly decrease). The vapor pressure of a liquidmixture can be predicted by Raoult's Law where the total vapor pressureis the sum of each component PFC vapor pressure times its mole fractionin the liquid. This means the most volatile component leaves faster andthe vapor pressure of the remaining PFC mixture slowly drifts toward thevapor pressure of the least volatile component in the mixture. Thiseffect is exacerbated as the higher vapor pressure PFCs also are ingeneral lower in molecular weigh so they also diffuse faster and havehigher water solubilities.

Examples of PFCs suitable for use in various implants described hereininclude: perfluoropropane, perfluorobutane, perfluoropentane,perfluorohexane, perfluoroheptane, perfluorooctane, perfluorononane,perfluorodecane, perfluorooctylbromide, perflubron, andperfluorodecylbromide. As explained above, two or more PFCs can becombined to form a liquid mixture with a particular vapor pressureaccording to their mole fraction in the liquid. A preferred range ofvapor pressures for a PFC element in one or more embodiments is around50-200 cm H₂O. In other embodiments the preferred range of selectedvapor pressures for a PFC element is around 100-150 cm H₂O. In otherembodiments, for example in the bladder, the preferred range of selectedvapor pressures for a PFC element is around 115-130 cm H₂O, around 120cm H₂O or around 115-117 cm H₂O. For example, in one embodiment amixture of about 0.5 mole perfluorooctane and about 0.5 moleperfluoroheptane can result in a vapor pressure of between around 115and 130 cm H₂O at 37° C. In another example, a mixture of 0.545 moleperfluorooctane and 0.455 mole perfluoroheptane can result in a vaporpressure of about 120 cm H₂O. The preferred range of selected vaporpressures for a PFC element can be based in part on pO₂ of theanatomical structure. Thus, for example, areas of the body with a pO₂similar to that of the bladder can also use a similar PFC pressurerange. As pO₂ increases the desired PFC vapor pressure range decreases.

Volumes of the PFC element are generally limited by the volume of theorgan or tissue site in which the implant containing the PFC element isimplanted and by the duration in which the pressurization is intended tobe maintained. A preferred range of volumes for a PFC element within animplant according to one or more embodiments is around 0.1-10 ml andmore preferably around 0.2-0.6 ml in certain applications involving theeye or the bladder. Total volumes of implants such a balloons or cellsaccording to one or more embodiments can vary from 0.1 ml to 1.0 L.

The preferred volume for an implant will vary based on a variety offactors. The following example demonstrates some of the considerationsfor the total volume of an implant in a particular application. Apressurized implant is added to the bladder in order to attenuatepressure pulses in the bladder associated with stress urinaryincontinence leakage. The clinical efficacy (preventing leakage) isincreased by increasing the volume of the implant. In testing, it hasbeen determined that efficacy increases proportionally to size.

The functional capacity of a typical urinary bladder is commonly in therange of 200 to 300 ml. This depends on many characteristics such asgender, age, health status, etc. If the implant is too large it willimpact the bladder's ability to perform its primary function of storingurine. “Residual volume” is a parameter that is commonly measured byurologists and it describes the measured quantity of urine remaining ina patient's bladder after they have completed voiding (i.e. they thinkthey are empty). Based on the experience of urologists it has beendetermined that a balloon as large as 30 to 40 ml will not likely benoticed by patients, specifically with regard to increasing theirfrequency of urination. Thus, a preferred balloon volume for the bladderis between 20 and 30 ml.

Selection of a PFC and Enclosure Skin Tension System

As discussed supra, one equation for the desired PFC vapor pressure is:

P _(PFC) =P _(anatomical environment/hydrostatic avg) +P _(Skin-tension)−P _(Dissolved gas)  (9)

It is possible that a skin tension and PFC could be chosen so that thetwo associated parameters for these characteristics are much, muchlarger than the other two parameters (for example between 5 and 20 timesand preferably 10 times). For example in the bladder, ifP_(Bladder-average) is on the order of 15 cm H₂O above atmosphericpressure, or about 1015 cm H₂O absolute pressure; P_(dissolved-gases) ison the order of 880 cm H₂O; then a balloon could be selected so that itsskin tension pressure is 10,000 cm H₂O or greater, and a PFC could bechosen with a vapor pressure that is approximately the same amount.Then, in theory, a system could be designed that is relativelyindependent of the average anatomical environment pressure, here bladderpressure, and independent of the gas tension of dissolved gases. This isbecause, in this example, P_(PFC) and P_(skin-tension) are approximatelyequal, and much larger than the other two terms. Similarly, devices usedin other anatomical environments and applications such as ophthalmic,vascular, cardio-vascular, renal, pulmonary, intracranial, etc., couldbe designed with similarly appropriate and corresponding skin tensionand P_(PFC) values.

Implant Compliance

An objective of certain devices according to one or more aspects of thedisclosure is to supply compliance, dV/dP or a maximum change in volumewith an elevation of pressure (P_(h), hydrostatic pressure). Thepresence of an elastic skin only slightly reduces the compliance of thedevice. Since the compliance (dV/dP) of a gas obeying Boyle's law,P₁/P₂=V₂/V₁, is inversely proportional to the absolute pressure of thegas inside the device (P_(g)); as long as the added skin pressure(P_(skin)) is significantly less than one atmosphere (760 mm Hg, 1,033cm H₂O), the compliance of the gas is only slightly reduced with anelastic skin (a skin pressure of 5% of an atm, 50 cm H₂O, has 95% of thedV/dP of gas without a skin).

The other cause for a reduction in compliance is that, as the devicevolume reduces under an external pressure increase, the pressure causedby the skin goes down, relieving some of the added pressure and reducingsome of the volume change. This effect is controlled by the slope of thevolume vs. pressure curve (V/P curve) of the device, which in turn isdetermined by the skin materials and geometry. In the case of aninelastic bag, the V/P curve starts at zero pressure at zero volume andthen jumps vertically to the volume when the bag is full (a fullinelastic bag does not stretch with more gas pressure inside) for anymeasurable pressure. This bag has no compliance at pressures thatcompletely fill it, as the slope of the V/P curve is zero. On the otherhand, a skin that is very stretchy/elastic (e.g. thin silicone) has avery gradual change in skin pressure as the volume changes (can bedesigned to have a large V/P slope at the operating volume) and onlyslightly reduces the device compliance. The small magnitudes of theseeffects are seen in a toy latex balloon that changes diameter/volumenearly as much as a free gas when the barometric pressure or altitude ischanged.

The above compliance reducing effects of the skin are reduced and insome cases overcome by the compliance increasing effects of the presenceof PFC vapors, e.g. their ability to condense when compressed.

The vapor pressure of the PFC may be chosen to inflate the device atequilibrium to a volume where the V/P curve of the device has a verylarge positive slope or in other cases just below where the slopedecreases, thereby limiting maximum volume.

The V/P curve of a device can be calculated from the known elasticproperties of the material (stress/strain relationship) and mechanicalprinciples (the law of Laplace, P_(skin)=2 times the skin tension overdevice radius). In many cases it may be better to measure the V/P curveof a device by inflating it with any fluid (e.g. air or air plus PFC)and then adjusting it. The device V/P curve can be adjusted, forexample, by lowering the V/P slope using a thicker or stiffer skinmaterial. Modifying the geometry of the device can also adjust thecurve, e.g. the 1/radius law above means that a long small radiuscylinder will have a shallower, lower slope V/P curve than a sphere ofthe same volume.

The V/P curves of the various devices described herein can be modifiedin many ways using unique geometry, so that even essentially inelasticmaterials can have an elastic V/P curve. FIGS. 34A-35D illustratefeatures of implants 66 including various skin geometries which affectthe V/P curve of the implant. In certain embodiments, sinusoidaloscillations in the device surface or dimples (positive or negative)like a golf ball, turn flexing moduli into elongation of the shape. FIG.34A shows a side view of a corrugated implant 66 with ridges 106 thatinitially provide little resistance to expansion but upon full inflationstraighten out and form a smooth inelastic surface resisting furtherexpansion. FIG. 34B shows the cross-section of the expanded implant 66.In other embodiments, coiled cylinders or clusters of small spheres vs.single spheres are utilized to reduce inflation radius. Otherembodiments, such as a relatively flat envelope, may comprise turningflexing moduli into thickening of the shape.

In some embodiments, cross ribs can be used to add stiffness to the V/Pcurve. FIGS. 35A and B depict an implant 66 with frame or “x” lattice108 that can compress laterally and elongate vertically. Thus, in thisembodiment the implant can initially form a flat disc or plate and thenexpand upwards as indicated by the arrows. As shown in FIGS. 35C and D,certain implants 66 can be at least partially enclosed in an inelasticnet 110 to stop growth or steepen the V/P curve at a certain volume. Thenet 110 could be attached or unattached to the device. Inelastic chordscould be included in other device shapes like in tires with chords.Alternatively, the net 110 can be a pattern formed of the same materialas the implant 66 but of a different thickness.

Providing Skin Tension Bias to Sustain Implant Volume in ChangingPressure Environment

Various embodiments of implants described herein comprise balloons,cells or enclosures comprising a porous vessel where internal gases andexternal gases dissolved in the body fluid interchange over time. Suchballoons will tend to expand or contract as the result of an imbalancebetween the outside “loads” and the internal forces supporting theballoon. With correct PFC vapor pressure selection a small bias can becreated where the balloon will grow until the tension in the polymerskin counteracts the bias of the PFC. The bias can be defined as the sumof all the partial pressures inside the balloon (PFC+air) minus theexternal sum of gas tensions or load in the surrounding environment.Turning to the equilibrium equation discussed previously, the PFCelement in this embodiment should be greater than or equal to the otherfactors:

P _(PFC) ≧P _(anatomical environment/hydrostatic avg) +P _(Skin-tension)−P _(Dissolved gas)  (11)

A balloon's internal pressure verses volume can be plotted as shown inFIG. 36. In the region from about 0 to 14 ml of volume, designated as upto “A”, the “balloon” is essentially a bag of air with zero skintension. At about 14 ml the bag becomes a balloon. Increasing amounts ofvolume put stress on the skin of the balloon and exert pressure on theinternal gases (as in the region around “B”). Depending upon the balloonmaterial and construction, this region of the graph showing theadditional volume being gained will be fairly linear. This is analogousto the elastic region of a stress vs. strain curse, which will remainlinear until either the elastic limit of the material is reached or thematerial fails.

As the volume increases, the balloon continues to stretch until the wallthickness decreases such that the balloon no longer exerts increasinglevels of force on the internal gases. At this point the ballooncontinues to increase in size, however, the pressure inside the balloonlevels off and eventually drops before the balloon fails. This area isdesignated with the letter “C”. In balloons that yield, either due tomolecular motion or thinning of the wall, this region of the graph canshow slower growth or even diminishing pressure with added volume. Theactual shape of the curve is material dependent. The shape shown, forexample, is consistent with the behavior of silicone. Similar graphs canbe made for other materials.

In the region before “A” and the region designated by “C” the balloon isunstable and tends to change volume as the result of gaseous interchangeacross the skin barrier. Balloon stability is created when a positivebias exits where the sum of the internal partial pressures is greaterthan the external gas tensions by an amount less than the height of thecurve at “C”, approximately 30 cm H₂O in this example. The positive biaswill increase the balloon's volume until the skin tension increases theinternal pressure to offset the bias. At this point the balloon will bestable. It would take more internal pressure than exists within theballoon to further increase in volume, and it is not able to shrink asthe positive bias forces the balloon volume higher than the bag region(before “A”).

In this way a balloon can be engineered to remain stable in volume (asopposed to completely shrinking or expanding until failure) overextended periods of time while experiencing changes in pressure. Thiscan be done by selecting a PFC with a slight bias over the anticipatedload but, counteracted by the skin tension profile of the balloon forthat pressure range.

One method of controlling the size of an air and high vapor pressuremedia filled porous balloon insitu utilizes the skin tension in theballoon wall to offset a purposely created difference between theexternal load and the internal resistance. This would be unnecessary ifit were possible to perfectly set the PFC vapor pressure to offset theexternal load. However, because the pressure in the bladder fluctuatesand different patients have different average bladder pressures it canbe useful for a device to have some tolerance to naturally occurringfluctuations and/or to be able to be used in different patients. Byutilizing the skin tension in the manner prescribed here tolerance canbe added to the naturally occurring variations in average external loadon the balloon.

It has been shown that in the initial under-filled or “bag” region “A”of the curve or in the post-yield region “C”, it is extremely difficultto control the balloon volume over time. In order to control the balloonvolume over time in these regions, the PFC vapor pressure would have tobe set precisely and the variation within and between patients wouldneed to be very small. Conversely, by using the increasing pressure withvolume nature of the “elastic” region “B” of the curve the balloon canfind its own equilibrium and become stable in volume.

For example, if the average external load across a population were 100cm H₂O and the average external load across the patient populationvaried from 90 to 110 cm H₂O then the PFC may be blended to yield avapor pressure of 120 cm H₂O. Assuming the balloon is not initiallyover-filled, the balloon would gain volume by sucking dissolved gassesfrom the surrounding liquid environment. As the balloon increased involume the pressure would go up due to the tension created in theballoon wall. This wall stress will offset the excess vapor pressure ofthe PFC blend and the balloon will stop growing and be at equilibrium.

Another advantage to designing the system to equalize on this part ofthe curve is that the balloon volume changes little with changes in theexternal load. This is because in order to offset small changes inexternal load a relatively large change in pressure is required.

The slope of the pressure vs. volume curve in this region is the resultof the elastic modulus of the material and the geometry of the balloon.The acceptable limits of this curve are bounded by comfort andirritation which can be affected by high sloped (or stiff) balloons andpoor volume control from balloons with low slopes in this region of thecurve. Slopes of between 1 and 20 cm H₂O/ml of volume have been shown toprovide bounds to these criteria. Slopes between 3 and 8 cm H₂O/ml ofvolume are preferred. As previously mentioned the slope can be designedinto the balloon by the selection of material (elastic modulus) andgeometry (shape and wall thickness).

Limiting Implant Expansion

In another embodiment two or more PFCs with different vapor pressuresare mixed to give an average vapor pressure based on the mole fractionof the components. As the PFC mixture diffuses out of the device overtime the more volatile component will diffuse proportionately to itsmole fraction in the mix, therefore the mole fraction of the highervapor pressure component will go down and the vapor pressure of the mixwill likewise be reduced. This phenomenon could be used to control theultimate size of the balloon. As the balloon expands, the vapor pressureof the PFC mix will go down placing an upper limit on balloon volume.

In some embodiments, the skin tension of the balloon could be usedadvantageously to limit balloon expansion. As the balloon expands, thetension of the balloon material will increase until the excess gaspressure in the balloon will be offset by the tension in the balloonskin.

In addition, just as skin geometries and other features of the implant66 can change the V/P curve; these same or similar features can limitexpansion, deflation or the rate of change of the implant. Thecorrugated implant of FIGS. 34A and B can allow expansion with thedisclosed ridges 106 and limit expansion with this same feature. Theridges 106 can initially provide little resistance to expansion but uponfull inflation straighten out and form a smooth inelastic surfaceresisting further expansion. The frame or “x” lattice 108 and the net110 of FIGS. 35A-B and 35C-D, respectively, can both be used to limitexpansion of the implant 66. FIGS. 37A and B show additional featuressuch as curvilinear elements 112 or interlocking elements 114 disposedon or within the membrane of an implant 66 operable to limit expansionalong one or more axis.

In one embodiment, an implant has a high surface to volume ratio toaffect a rapid rate of change. The implant shape can be selected fromcylindrical, spiral, or ridged. In another embodiment a slow rebound orrapid inflation is desired and thus a low surface area to volume ratiois desired and a spherical design is selected.

In a further embodiment the quantity of PFC in a balloon could be usedto limit expansion. A precise quantity of PFC could be added to theballoon such that as the balloon expands the PFC would volatilize tomaintain its partial pressure until the PFC liquid reservoir isdepleted. The PFC gas would then dilute with further expansion and theinternal pressure of the balloon would be limited.

Devices described herein containing PFC and other gases can be placedinto pressure equilibrium with the environment in which they aredeployed. Since no natural environment is truly at constant pressure,the balloon system would need to gain external gases during low externalpressure times and lose gas during high pressure times. The loss of gaswould need to balance with the gain of gas for long term stability.

Controlled Expansion and Reduction

In another embodiment, a controlled expansion device is provided that isoperable to expand or contract over time at a controlled rate. The ratecan be controlled, for example, via selection of an enclosure with asuitable diffusion rate and selected PFC element for its vapor pressureproperties. Unlike other embodiments, in this case the PFC element willhave a significantly greater value than that selected for equilibrium,perhaps 1.5-10 times greater, thus the driving equation is as mentionedabove:

P _(PFC) ≧P _(anatomical environment/hydrostatic avg) +P _(Skin-tension)−P _(Dissolved gas)  (11)

For example, in breast augmentation/reconstruction surgery, as explainedbelow, it could be advantageous to place a small balloon at the futureimplantation site with the capability of expanding slowly over severaldays or weeks creating a pocket in the tissue. This could facilitate theplacing of the implant with minimal discomfort or trauma to thesurrounding tissue. In one embodiment, the device inflates to full or100% volume in a period of a minute to a month. This concept could beapplied to any implant procedure in which space needs to be made for theimplant itself, or another implant or transplanted organ. Implantsaccording to one or more embodiments could optionally include implantedelectronic monitoring and regulating devices to monitor and control theexpansion or contraction of such devices.

Illustrated in FIGS. 38A and B are breast augmentation or reconstructionimplants and devices 66. The devices 66 can be used to create space fora different implant, such as a silicon gel or saline breast implant. Insome embodiments, the device 66 can remain within the body, aftercreating, forming space, and/or stretching the surrounding tissue. InFIG. 38A, an inflatable implant 66 is placed within breast tissue 116.By charging the implant with a selected PFC element, the rate ofexpansion of the implant 66 can be gradual and controlled, therebyreducing stretch marks or other damage. FIG. 38B shows anotherembodiment in which an implant 66 is placed between the ribs 118 andmuscle tissue 120 to create space for a different implant.

A controlled reduction balloon or piston system could be used to slowlyallow tissue healing or reestablishing load bearing capability overtime. For example, a piston-like device could be constructed such thatthe slow expansion or shrinking of the PFC-related gas volume causes thecylinder within the piston structure to move in or out. In oneembodiment the device deflates to about zero volume or length in aperiod of a minute to a month. This could be advantageous in aftercertain surgeries or to assist the healing process. For example, in FIG.39 cuff-like and rod-like implants 66 are shown connected to vertebrae122. A cuff-like implant 66 can surround one or more vertebral bodies. Arod-like implant 66 can be connected to opposing spinous processes 123with fasteners 124. After spinal surgery, one or more of these types ofimplants could be used to temporarily support the vertebrae. Slowly overtime (days or weeks, months) the implants 66 would add load to thehealing vertebrae. Likewise, knee surgery, spine surgery, shouldersurgery, hip surgery or other procedures involving broken bones ordamaged joints would be potential applications.

Controlled expansion/reduction devices according to one or moreembodiments can create space, maintain space, occupy space, or establishan attenuative capacity within or at a space. Further examples ofparticular applications for controlled expansion/reduction deviceinclude site preparation for breast implants, calf implants, buttockimplants, transplanted organs, plastic surgery sites, facialreconstruction, and spinal repair. Similarly a controlled reductionballoon could be used where large amounts of soft tissue have beenremoved such as after liposuction or organ removal.

Controlled reduction implants could be made from bio-absorbable polymersthat sacrifice material over time and shrink or become more or lesselastic or are completely dissolved and absorbed when deflated.

Tissue Expander

Smooth muscle in the human body is an example of a viscoelasticmaterial, meaning that it exhibits a phenomenon known as “stressrelaxation.” When a muscle is stretched to a new length, it respondsinitially with a significant increase in force. This is the elasticresponse of the material. This is followed by a decline in force that isinitially rapid, and then continuously slows until a new steady force isreached. Correspondingly, if a muscle is subjected to a constant force,it will elongate slowly until it reaches a new length. This phenomenon,the complement of stress relaxation, is known as tissue creep. [MedicalPhysiology: Principles for Clinical Medicine; By Rodney Rhoades, DavidR. Bell; 3^(rd) Edition; Published by Lippincott Williams & Wilkins,2008; page 166]. These phenomena are commonly exhibited when an athleterunner stretches their muscles after exercise. In this case, a force isapplied, and the muscle stretches until a new muscle length is reached.

According to one aspect of the disclosure a tissue expanding implantcharged with PFC media is placed within or between viscoelastic tissuesuch as muscle or skin. Such tissue will exhibit stress relaxation andthere will be an initial high force exerted on the tissue expandingballoon, which will gradually decrease until a new lower constant forceis reached. Unlike a conventional tissue expanding balloon, it is notnecessary to access the tissue expanding implant and refill itperiodically to continue the process of stressing, then stretching andrelaxing the tissue. Not having to access the implant to refill it isparticularly advantageous in applications requiring percutaneous accesswith its associated risk of infection and expense.

In one embodiment, a PFC mixture is combined with a specially selectedballoon membrane material to provide a tissue expanding implant thatautomatically expands without requiring repeated percutaneous access. Anadditional benefit is that the design of such embodiments can inherentlyprevent uncontrolled expansion of the expander which will serve tominimize undesirable effects such as tissue rupturing, or ischemia.

For example, in the breast augmentation or reconstruction examplediscussed above and shown in FIGS. 38A and B, because the implant 66 ischarged with a selected PFC element the viscoelastic tissue can beslowly moved and stretched without having to re-inflate the implant 66and without a pressurized gas source.

In one embodiment, an implant filled with air and a small quantity ofPFC is placed into tissue or between layers of tissues where expansionis desired, for example under the skin and above the muscle of apatient's abdomen. In another embodiment, the implant can be used as atissue expander in preparation for a skin graft of the newly stretchskin. The size of the implant and the quantity and vapor pressure of thePFC can vary based on factors including the size and weight of thepatient, the patient's age, their health, the purpose of the tissueexpansion, the gas permeability of the implant material.

An inflatable implant filled only with air would deflate over time dueto the pressure exerted on it by the tissue. The addition of the PFCsets up two equilibriums such that:

P _(Inside Balloon) =P _(Exerted by tissue) +P_(Balloon Skin-tension)  (12)

And:

P _(Inside Balloon) =P _(N2) +P _(O2) +P _(other gases) +P _(PFC)  (13)

Over time, the gas partial pressure components(P_(N2)+P_(O2)+P_(other gases)) will equilibrate until they equal thegas tension of dissolved gas in the tissue and liquid surrounding theballoon. The gas tension of N₂ will be roughly the same as found inatmospheric air since the body does not metabolize nitrogen. The gastension of O₂ will vary depending on a variety of factors. Thus, theselection of the material and the PFC partial pressure are governingfactors in determining the pressure of the tissue expanding balloonimplant.

Coatings

Despite the hydrophobic tendencies and relative insolubility of PFCs inwater and bodily fluids, PFCs will diffuse out of certain enclosures.This can be minimized by various surface treatments including lubricitycoatings, anti-microbial coatings, acid or basic pH coatings, drugeluting or containing coatings, roughening, or establishing a positivelyor negatively charged surface. Both the interior and/or the exterior canbe treated and each could be treated in a like or different matter. Forexample they can be charged + on the outside and − on the inside orrough on the outside to form and capture bubbles and smooth on theoutside to be non-irritating. The inside and outside of the enclosurecan be hydrophilic or hydrophic, alternatively the inside and outsidecan be treated to have opposite attractiveness to water.

Examples of suitable coatings for various devices disclosed hereininclude: aqueous hydrogels on inside to prevent bubble formation, butylrubbers to hold in PFCs, metal coatings, nano-crystallized silver basedantimicrobial coating, polyvinylpryrrolidone based coatings, drugcoatings including duloxetine hydrochloride, nerotranmitters mediatingdrugs, analgesics, antiseptics, antibiotics, incontinence treatmentdrugs, anti-cancer drugs, cystitis treating drug, and oxybutynin.

Initial and Automatic Inflation

Certain embodiments of disclosure involve the inflation of implantsdescribed herein with initial infusions of various media, includinggases or liquids of air, nitrogen, oxygen, carbon dioxide, PFC, etc. Theinitial infusion can be before or after the device is implanted. Theinitial infusing can be delivered via a syringe, tube, capsule, ampule,cannulae or other known delivery devices. For example, any of thedelivery devices shown and described herein can be used (see FIGS.6-18).

In another embodiment, a self-inflating implant comprising a selectedPFC element and an enclosure at least partially permeable to nitrogenand oxygen is provided. After implantation, the PFC vapor will diluteany air component gases within the enclosure and cause the air componentgases in the anatomical structure to diffuse into the enclosure untilequilibrium is reached thereby inflating the enclosure device.

In one embodiment, a pressurized implant is adapted to inflate over timeto a selected volume or pressure and then deflate in response to anelevated pressure. For example, an implant is inserted within a bladderand inflates to a first selected pressure or volume. Upon theapplication of an external load or pressure, such as when the patientvoids the bladder, the implant reaches a second selected pressure, atwhich point the implant is adapted to rapidly decrease in volume as thehigh vapor pressure element within the implant condenses into liquid.When the external load is removed, such as, after the bladder is empty,the implant will gradually return to its first selected volume orpressure. Thus, by providing an implant operable to attenuate bladderpressure spikes within a certain range and then quickly deflate at thetime of voiding, a diminished and more comfortable volume is present atthe time of emptying of the bladder. Therefore, a more comfortabletreatment is effected.

Bubble Formation

In certain embodiments, a PFC permeable skin (e.g. silicone) is used. Inthese embodiments, the skin pressure of the implant at equilibrium isincreased because of the use of the PFC permeable skin. Also, the PFCpartial pressure is higher making the total gas tension (including PFC)at the implant surface higher than the hydraulic pressure. This willcause bubbles to grow on the implant surface.

When bubbles are attached to the implant surface, the PFC no longer hasto go through the diffusional barrier of water. Thus, a constant streamof bubbles stabilized with PFC are generated. This can be an advantagein some applications such as the bladder where more compressible volumeis generated, but can be a detriment in some uses, such as in the eyefor example. Though in either case, the generation of PFC containingbubbles causes a much faster loss of PFC from the implant.

These PFC stabilized bubbles contain only very small masses of PFC andthus, while more stable than air bubbles, will not stay inflated forextended periods. The PFC bubbles will collapse as PFC is taken awayfrom the local environment.

A condition for bubble growth prevention is that the PFC diffusionalresistance through the skin has to drop the device surface PFC gastension (cause a PFC concentration gradient) equal to more than the skinpressure P_(skin). (P_(PFC)−T_(PFCsurface)>P_(skin) where T_(PFCsurface)is the gas tension of PFC at the device surface).

Bubble formation can be prevented with a low skin pressure atequilibrium or having a skin with a higher diffusional resistance toPFCs. If higher skin pressures are used, lower PFC permeability skinscan be provided to prevent bubbles. Reducing the outer surfaceconcentration of PFC bubbles will also reduce their formation. Suchconditions can include fluid movement that flushes away the surface PFCbubbles.

In another embodiment, bubbles may be prevented by coating the insidesurface of the implant with an aqueous gel. In some embodiments, the gelcan be about 1 mm thick. In another embodiment water is used to coat thesurface, as it is an excellent barrier to PFC diffusion while stillallowing soluble gas diffusion through the implant.

The gel can be any biocompatible gel with a high water content (e.g.hydro-gels, starch, hydroxyethyl starch, poly-acrylamide, hyluronicacids, dextrans, carboxymethyl cellulose, purified gelatin, modifiedcollagen, water filled silica “smoke”). In some embodiments the gel isdried onto the inside of the implant in a thin layer and spontaneouslyrehydrates and expands in thickness when exposed to body fluids, such aswhen water permeates through the skin. The gel can cause the PFCconcentration gradient of the first few millimeters of fluid on theoutside of an uncoated device, to now occur on the gel layer inside thedevice. The gel layer is subject to the skin pressure and thus nobubbles would form inside or outside of the implant.

Generator

In one embodiment PFC is contained in a porous enclosure, balloon, orenvelope with or without additional gases. The porosity of the enclosureis selected such that the PFC diffuses through the balloon material and,since it is highly hydrophobic, does not dissolve in the externalliquid, but would form bubbles on the surface of the balloon. Thissystem could be used as a “gas bubble generator” in a body cavity. Theadvantage could be the addition of gas (compressible) to a liquid(incompressible) system thus increasing the compressibility of theoverall fluid system and its ability to attenuate pressure spikes orsudden changes in pressure. Such an embodiment may also attenuate twoseparate pressure ranges, one corresponding to the compressibility ofthe bubbles and another corresponding to the compressibility of theballoon or envelope.

Packaging

There may be situations where it would be desirable to store PFC in whatessentially amounts to a container made of a gas permeable material suchas a prefilled implant balloon. Consider, for example, a siliconeballoon containing PFC, as described above. This balloon exhibits somevery desirable characteristics such as staying inflated for extendedperiods of time when immersed in bodily fluids. Such a balloon could befilled with only PFC, or with PFC plus air, when it is already residingwithin a location within the body; or at the time when it is placedinside the body. However, it may be desirable for manufacturability orusability reasons to have a device “preloaded” with a quantity of liquidPFC. For example, this could be used to simplify the clinical procedurein which such a device is inserted into the body. Instead of insertingthe balloon and then filling it; the procedure could involve inserting adevice that already contains a quantity of liquid PFC. This PFC could,over time, induce other gases found in the balloon's externalenvironment, to diffuse into the balloon, achieving a concentration orgas tension equilibrium, and causing the balloon to inflate on its own,in-vivo. In some embodiments, a delivery device with a preloaded implantcould be packaged together.

In some instances a preloaded device could, over time, lose its PFCcontents. It will also inflate itself, before insertion, if stored incontact with air. Even if the balloon is physically constrained, so thatit cannot expand, a small amount of PFC vapor will form within theballoon. This will diffuse across the gas permeable walls of thesilicone, and exit the balloon. Over time, all of the PFC will exit theballoon in this manner. If the PFC-containing-balloon is placed within agas impermeable pouch, such a foil pouch, and all air is evacuated(vacuum packed), there will still be a situation where the PFC will exitthe balloon slowly and collect in the pouch when exposed to atemperature gradient, and will inflate the foil pouch over long storagetimes if the pouch has even a very small gas permeability, continuinguntil either a force equilibrium is formed with the inflated foil pouch,or until all of the liquid PFC within the balloon is gone.

Accordingly, one embodiment, shown in FIG. 40, involves a pre-loadedpackage or gas impermeable pouch 126 with a quantity of liquid PFC 128in the pouch external to the implant 66 which is also preloaded a with aquantity of PFC. In this way, the device has the same PFC vaporconcentration/partial pressure on the inside and the outside. Thereforethere is little or no diffusion gradient to induce loss of PFC from thedevice. In this way the supply of liquid PFC 130 within the device isnot depleted prior to implantation as the device is kept in storage andimplant 66 is maintained in a deflated state until it is within thebody. Moreover, selecting a slightly higher vapor pressure PFC 128outside of the implant 66 would ensure deflation of even a partiallyinflated implant, during storage.

After the particulars of the implant have been selected according to thevarious selections above, the implant can be prepared and then implantedinto the treatment site in the body. Various non-limiting examplesfollow which demonstrate certain aspects of the implant in certain partsof the body.

Example 1

In one illustrative embodiment, intraocular implants or otherimplantable devices described herein comprise a silicone elastomer,polyolefin or acrylic balloon that may be used to contain air and theselected PFC vapor. The balloons may range in volume from 0.1milliliters to 2 milliliters.

The eye is a challenging environment in which to deliver and maintainthe inflation of a therapeutic implant because the intraocular pressureexceeds atmospheric pressure and the oxygen tension in the anterior andposterior segments of the eye is known to be significantly less than theoxygen tension in normal atmospheric air. In the absence of a PFC, theballoon will deflate due to the intraocular pressure (TOP) exceeding theoxygen and nitrogen tensions in the anterior and posterior segments ofthe eye. The oxygen tension in the normal atmosphere is approximately159 mm of Hg. The oxygen tension in the intraocular environment rangesfrom 10 to 30 mm of Hg. The nitrogen tension in the intraocularenvironment, as well as that of other gases in normal atmospheric air(i.e. argon, helium), is approximately the same as that of normalatmospheric air. Thus, the gas tension deficit in the intraocularenvironment is primarily due to reduced level of oxygen. For the purposeof this example, the oxygen tension in the intraocular environment isdefined as 20 mm of Hg. Accordingly, the gas tension deficit is 139 mmof Hg (159 mm of Hg minus 20 mm of Hg). The total gas tension in theintraocular environment is approximately 621 mm of Hg (594 mm of Hgcontributed by nitrogen, 20 mm of Hg contributed by oxygen and 7 mm ofHg contributed by all other gases found in normal atmospheric air).

If the TOP is 775 mm of Hg, a PFC mixture is needed to deliver a minimumvapor pressure of 154 mm of Hg (775 minus 621 mm of Hg). This can beaccomplished with a mixture of perfluorohexane and perfluoroheptane. Theratio of the two PFCs is determined using a weighted average calculationon a molar basis. To assure that balloon inflation is maintained, thevapor pressure of the PFC mixture may be increased by 1-100 mm of Hg. Inthis case the skin tension of the balloon will offset the amount bywhich the PFC vapor pressure exceeds the TOP minus the total gas tensionwithin the fluids surrounding the balloon. The additional vapor pressurewill compensate for normal diurnal fluctuations in IOP.

To maintain inflation, the balloon is charged with the PFC mixture atthe time of inflation or at any point following implantation. The amountof PFC which is added is determined based upon the loss rate of PFCthrough the balloon walls and the desired duration of inflation. For aballoon composed of a high density polyethylene, a 50 microliter PFCvolume can be expected to maintain inflation for 6-18 months; the actualduration of inflation will depend upon a variety of factors, includingthe balloon wall thickness, surface area, and any coatings ortreatments.

Example 2

Self-inflation of a balloon in an ophthalmic application can be achievedwith a balloon composed of a material which is permeable to oxygen andnitrogen. At the time of implantation, the balloon is charged with thePFC mixture and a minimal amount of air (e.g. 1-25 microliters). Theballoon may also be filled with additional air to reduce the timerequired for complete balloon inflation. Shortly after the time ofimplantation, the PFC vapor pressure exceeds the IOP in the eye minusthe total gas tension in the fluids surrounding the bladder.Self-inflation will occur as a result of diffusion of oxygen andnitrogen, from the vitreous in the case of a posterior segment placementor from the aqueous in the case of an anterior segment placement,through the walls of the balloon as the PFC vapor has diluted thesegases, inside the balloon, to partial pressures that are less than theirgas tensions in the contacting fluids. The time required forself-inflation will vary from several days to several weeks dependingupon the total gas tension in the balloon as well as the rate of gastransmission through the balloon wall. The time required forself-inflation is inversely related to the total gas tension in theballoon.

Example 3

To assure that balloon inflation is maintained, the vapor pressure ofthe PFC mixture may be increased by 1-100 mm Hg relative to the levelthat matches the IOP/fluid total gas tension differential. In this casethe skin tension of the balloon will offset the amount by which the PFCvapor pressure within the balloon exceeds the equilibrium value. Theskin tension will pressurize the balloon gases until the oxygen,nitrogen and other gas partial pressures within the balloon rise tomatch their gas tensions in the contacting fluids. The additional vaporpressure will compensate for normal diurnal fluctuations in IOP.

For internal balloon gas equilibrium pressures that exceed the IOP, theskin tension of the balloon counterbalances the excess gas equilibriumpressures (defined as equilibrium pressure minus IOP or the PFC vaporpressure plus the total fluid gas tension minus the IOP). The mechanicalcharacteristics of the balloon as well as its polymeric structure aresuch that the balloon resists overexpansion by the excess gasequilibrium pressure. The modulus of elasticity, wall thickness andcrosslink density should be optimized to avoid overexpansion.

Specifically, a silicone elastomer balloon composed of a silicone with aShore A hardness of 30 and wall thickness of 0.20 millimeters can resistoverexpansion produced by an excess gas equilibrium pressure of 20 mmHg.

Example 4

FIG. 41A illustrates a side view of a human head 132 implanted withvarious inflatable therapeutic implants 66. The implants 66 can comprisea flexible membrane enclosure, balloon, or envelope and are charged witha high vapor pressure media such as PFC. In some instances the implantcontains a valve and may be at least partially filled with air oranother gas at some point during the implantation process. The implants66 can be shaped, coated, and comprised of various materials asdescribed throughout this disclosure. As shown, certain implants 66shown have been implanted in the cranium to attenuate intracranialpressure, prevent aneurysms, ameliorate airflow conditions contributingto sleep apnea or snoring, create space, stabilize tissue, or as part ofa reconstructive surgery. Other implants 66 are shown implanted withinthe sinus, against the palate, within the gums, behind the cheekbone andalong the jaw. The implants 66 can be delivered through open surgery,percutaneously, nasally, orally, or ocularly.

In one embodiment, one or more implants 66 are implanted and theninjected with high vapor pressure media. In another embodiment, one ormore implants 66 are implanted and then injected with high vaporpressure media and a gas or air. In other embodiments, the implant 66 isimplanted and is fully charged with PFC media. Over a selected period oftime the implant 66 will expand until restricted by the enclosure orsurrounding tissue. As described above, the implants 66 can be adaptedto exhibit controlled expansion and/or reduction. In one embodiment, theexpansion of the implant 66 is limited to expand or contract againsttissue in order to align facial bones as part of a reconstructivesurgery.

FIG. 41B shows a top view of a head 132. In this embodiment inflatabletherapeutic implants 66 are used to constrict two tumors 134. Oneimplant 66 is shown as a sleeve 136 that has been placed about aperiphery of the tumor 134. A second implant 66 is shown as a sheet orpatch like 138 embodiment with two anchors 124 used to anchor theimplant against an interior surface of the cranium 140. The innersurface of the implant 66 expands or inflates over time and constrictsthe tumor 134 and/or blood flow to the tumor 134. In certainembodiments, the tumors are prohibited from growing; in otherembodiments, the tumors are reduced in size.

FIG. 41C shows another embodiment of an implant 66 used to stretch thescalp for harvesting and replanting hair. The implant 66 is shownimplanted between the skin 141 and the cranium 140. Over time theimplanted devices can expand and stretch the tissue.

Example 5

In FIG. 42A several versions of an implant 66 are provided for treatingbones. Shown is a piston-like implant 66 connected with anchors 124 toopposing ends of a long bone 142, such as a femur. The piston-likedevice could be constructed such that the slow expansion or shrinking ofthe PFC-related gas volume caused the cylinder within the pistonstructure to move outwards or inwards. After some traumatic injuries, apatient can be left with one of the long bones in the body too short,for example, one femur shorter than the other. The above embodiments canhelp treat such situations.

Also illustrated are two versions of cuff or belt like devices forcompressing or supporting bone. One inflatable cuff device is shownanchored to the bone 142 with anchors 124 and the other is simplywrapped around the bone. The cuffs are charged with a selected PFCelement and the membranes are selected to exhibit a desired compliancein order to stimulate bone growth or support a weakened or fracturedsection of bone. In this arrangement the bone is under compression,however, as shown in FIG. 42B, an internal rod-like or piston implant 66can alternatively be used to expand the bone or place it under tension.FIG. 43 illustrates yet another application of an expandable orinflatable therapeutic device as used in the rehabilitation of thespine. Shown is a functional spinal unit 143 having opposing vertebralbodies 122 and an anulus fibrosis 144 surrounding a nucleus pulposus146. Therapeutic implants 66 to support load, stimulate growth, orcompact or compress cancelleous bone are shown implanted within theanulus, and within a vertebral body.

In FIG. 44, a knee or elbow brace 148 is illustrated having an upperinflatable cuff 149 charged with a selected PFC element, a closuredevice 147 for providing initial fitting around a limb coupled by hingedmembers 145 to a lower inflatable cuff 149 also charged with a selectedPFC element. This embodiment is particularly advantageous because thePFC element can be selected such that over tightening of the cuff 149can cause a certain threshold pressure whereupon the PFC media willcondense from a gas to a liquid resulting in a loss of volume andthereby loosening the cuff 149 and preventing circulation problems ordiscomfort.

In another embodiment as illustrated in FIG. 45, various implants 66 areimplanted among the tissues of a foot 139. Placement of implants 66charged with high vapor pressure media along the heel, ball, and aboutthe ankle can provide support and cushioning and stability for the foot.

Example 6

FIG. 46 illustrates the digestive system 113 and various implants 66providing treatment such as intraorgan space creation, appetitesatiation or cessation, attenuation, and constriction. Shown includecuff like constrictor devices 66 placed about the stomach 243, liver242, gallbladder 244, pancreas 245, appendix 249, bladder 251. Theconstrictor devices 66 comprise an inelastic outer band and an innerinflatable member charged with a PFC element. Such a device can be usedto shrink a diseased organ for removal or restrict an organ frombecoming enlarged.

Also shown are inflatable implants 66 containing selected high vaporpressure media elements disposed within the esophagus 241 enroute to thestomach 243. The implant 66 is shown being ingested through theesophagus 241 in an unexpanded state. The implant may then travel or bepassed at the termination of a programmed treatment cycle out of therectum 250 in a deflated or reduced volume state. The treatment cyclecan include expanding in the stomach or anywhere along the digestivetract for a desired treatment period and then deflated. In anotherembodiment a treatment implant 66 is placed in or adjacent lymphoidtissue to help clear out lymph. Various embodiments of implants 66described herein may have one or more states or profiles depending onthe stage of treatment including; a reduced ingestion or delivery state,an enlarged treatment state and a reduced, deflated, depleted, ordegraded removal state.

Example 7

Illustrated in FIGS. 47A-F are various anchor devices 200 havinginflatable components charged with PFC elements that expand afterdelivery. In certain embodiments at least a portion of the device 200 isprogrammed to contract, deflate, or disengage after a treatment period.

FIG. 47A shows an anchor device 200 comprising an inflatable membraneenclosure 302 charged with a selected PFC element. The enclosure isconnected via a connector 301 to an attachment site 300. The enclosure302 may comprise a coating or high friction surface.

FIG. 47B shows another anchor device 200 having an attachment site 300,connector 301, a pointed shaft portion 303 and one or more deployablebarbs 304 that deploy via the inflation of a piston or actuatorcontaining a PFC element after implantation.

FIG. 47C shows a device 200 implanted within and expanded beyond a bonesurface. In this example the device 200 is implanted within a vertebralbody 122 and the membrane enclosure 302 is expanded within thecancellous or trabecular bone tissue inside the vertebral body 122. Inanother embodiment, the anchor device 200 is inserted into or throughsoft tissue and the membrane enclosure 302 is expanded within or beyondthe tissue to establish the attachment site 300 to the tissue surface.

In FIG. 47D, a hollow organ such as heart, stomach, or bladder 251 isshown with an implant 200 comprising opposing inflatable enclosures 302connected via a connector 301. The connector can be used to applytension and move, displace or support the opposing walls of the organ.The inflatable enclosures are operable to establish or anchor theconnector to the opposing walls and are oversized relative to theconnector such that they are incapable of migrating through the wall ofthe organ once inflated via the action of the PFC element.

FIG. 47E illustrates a temporary anchor for a catheter 305 such as aFoley catheter. One or more lumens or membrane enclosures 302 areoperable to anchor or establish the device within a treatment site uponinflation via the action of the PFC element within the lumen 302.

FIG. 47F illustrates yet another anchor device 200 established alongopposing surfaces of a tissue. In this embodiment, opposing inflatableenclosures 302 are connected via two or more connectors 301 disposedthrough the tissue. The anchor device 100 can provide attachment site300 for a suture, support the tissue, or repair or block a defect 253 inthe tissue.

Example 8

In another embodiment there is provided a penile implant. FIG. 48Aillustrates a cross sectional view of a penis 259. Shown are the leftcorpus cavernosum 261 and right corpus cavernosum 262 and corpusspongiosum 263 all of which are surrounded by fascia and skin 260.Expandable or inflatable implants 66 comprising a membrane enclosure andselected PFC element are shown implanted in the each of the corpi and incertain embodiments encircling at least a portion of corpus or between acorpus and fascia or skin.

In certain embodiments, the implant 66 may comprise voids or passages239 to allow the flow of blood through portions of the implant 66. Inother embodiments, the implant 66 is spiral or coil shaped.

FIG. 48B shows the glans 264 of a penis 259 with an inflatable implant66 charged with a selected PF media element at least partiallyencircling a portion of the urethra 265. The implants disclosed hereincan be used to cause partial or full erection of the penis or to createspace within the penis so that other implants may be inserted.

Example 9

FIG. 49A illustrates a further embodiment in the form of an uretal stentanchor. Shown is a cross section view of a kidney 266 with a stentdevice 307 implanted within a ureters. One or more inflatable lumens 308containing a selected PFC media element have been inflated afterinsertion and have formed a friction fit with the inner contours of theureter. In another embodiment, as shown in FIG. 49B, the uretal stentdevice 307 comprises a coil or spiral inflatable anchor lumen 308.

Example 10

Turning to FIG. 50A, a cross sectional view of a heart 272 is shown.Various implants 66 comprising an inflatable enclosure and selected PFCelement are shown implanted in various locations to attenuate pressures,create space, change the tissue compliancy of cardiac tissue, orreorient heart valve leaflets.

In one embodiment, the heart is treated by implanting an inflatabledevice 66 as described herein within one or more of the left and rightaorta 273, 273′, left and right ventricle 274, 274′, pulmonary artery275, aorta 276, vena cava 277 or simply within cardiac tissue 278. Suchdevices may optionally comprise a connector or anchor for establishingto or within the implantation site. In another embodiment, a band, cuffor sleeve-like device is placed over the vena cava 277, pulmonary artery275, or over a least a portion of the heart 272 or pericardial sack asshown in FIG. 50B.

Example 11

One technical problem that may be solved according to one or moreaspects of the disclosure is modulating or reducing the consequence ofpressure spikes within the abdomen.

Various physical events such as laughing, coughing, sneezing, orinvolvement in physical activity, such as, running, jumping, or pickingup something heavy, can result in a sharp contraction of the abdominalmuscles. This contraction can cause a sudden spike in intra-abdominalpressure which can, in turn, cause a pressure spike within the organsand tissues in the abdomen. Such a pressure spike can be undesirable. Insome instances, damage to such structures can occur immediatelyfollowing the incident, or can evolve over time.

For example, urinary incontinence can arise from such a physical event.These physical events subject the bladder to increased intravesicalpressure. The bladder rests at the bottom of the abdomen. Abdominalpressure is exerted on the bladder in generally a downward direction andto a lesser extent from the sides. When the intravesical pressure in thebladder exceeds the resistance of the bladder's sphincteric mechanismleakage of urine can occur.

Moreover, the increased pressure event can also result in analincontinence. When the abdominal pressure increases there is acorresponding increase in the force exerted upon the colon. If thepressure in the colon exceeds the outlet resistance of the anus therecan be an involuntary loss of feces or gas.

In addition to incontinence, other pathologies or conditions can arisefrom pressure spikes within the abdomen. Hernia or prolapse are two suchexamples that can result from extreme or prolonged cycling ofintra-abdominal pressure. Persons with weakened portions of theabdominal wall caused from a variety of factors such as lifting, childbirth, or predisposition are particularly susceptible to hernia orprolapse.

For example, pelvic organ prolapse is common in women who haveexperienced multiple births; the bowel (rectocele), bladder (cystocele)or uterus (enterocele) can herniate into the vagina, or protrude outsidethe body. Sections of bowel can herniate through weakened muscle wallinto the scrotum of men (inguinal hernia). Also, it is common for peoplewho have had abdominal surgery to later sustain incisional hernias. The“jackhammer” effect of repeated or cyclical spikes of high pressureovertime can cause such hernias to occur. Accordingly, it is an objectof one or more embodiments to lessen the extent of intra-abdominalpressure spikes.

In one embodiment, a pressure attenuating balloon or device is placed inthe bowel, intestines, abdominal aorta, stomach, or along the digestivetract. The device may be a permanent implant and anchored to a tissuewall, free floating or friction fit with the organ or tissue structure.In one embodiment, an attenuator is sized to be too long and relativelyinflexible to be passable around a bend in the digestive tract. Inanother embodiment, an attenuator is arcurate or “U” shaped,corresponding to the natural curved portion of the digestive tract andis adapted to not rotate or pass beyond the curved portion. In oneembodiment, the device is ring, tube, or cylindrically shaped to allowthe passage of food, liquid, or waste. In another embodiment, a deviceis adapted to reside outside of the digestive tract but remain inpressure communication with it via a port, membrane, or wall. Such adevice could be attached to the outer wall or reside remotely within theabdomen with a connector or tube placed within or in pressurecommunication with the digestive tract.

Rather than attenuating the organ or sites within the abdomen that aresusceptible to pressure spike influence, another method involvesattenuating the abdomen itself thereby achieving a systemic result. In apreferred method, one or more pressure attenuators are placed at a sitewithin the abdominal space. In use, the attenuator could serve to limitthe peak abdominal pressure and the rate of increase in pressureresulting from an event. This reduction in pressure could have a similareffect to an intravesical balloon, and reduce stress incontinenceleakage. It could also reduce anal incontinence effects. Over time itcould assist in reducing the “jackhammer” effect of repeated highpressure spikes that result in hernias, prolapse or abdominal aorticaneurysm. An abdominal attenuator as described herein could also have abeneficial effect on abdominal aortic aneurysms, or hiatal hernias.

Various embodiments of implants for attenuating pressure, reversiblyoccupying or creating space can comprise one or more free-floatingballoons, enclosures, or expandable devices. In certain embodiments, thedevice is incorporated into one or more sheets of other material like apatch. Accordingly, textile implants that are placed into the abdomen torepair hernias can also be adapted to contain attenuator or expansileelements. Various devices or materials comprising such devices can besurgically anchored; mechanically wedged in place after implantation;free floating; permanent, temporary, or bio-absorbable; layers ofair-containing substances such as closed-cell foam; comprised of chainsof or strips of connected balloons or sheets of balloon material likebubble-wrap; coated with or constructed from lubricious materials,anti-bacterial materials, or anti-adhesion materials.

Balloon type constructs could be filled with air, PFC mixtures or othergases or combinations of gases and liquids. They can be durably inflatedor refilled periodically. If refillable, they can be refilled using asub-dermal injection port that communicates through a lumen to the lumenof the balloon. They can also be connected to a “radiator cap” typepercutaneous access system such as is used for the exchange ofcontinuous abdominal peritioneal dialysis fluid exchange, or for acolostomy. Elastic balloons can simply be injected into the abdomenpercutaneously through a needle.

In some embodiments a material that forms a solidified foam is used tocreate, in effect, a closed cell construct containing multiple pocketsof encapsulated air. In some embodiments, temporary or permanentattenuator devices are used to reduce peak pressures in the abdominalregion to prevent trauma to organs or tissues during procedures or aftersurgery to reducing post-operative pain.

Various intra-abdominal devices described herein can also be adapted toserve as platforms for drug delivery, pressure sensing, monitoring,storing or emitting data such as electromyograms, electrocardiograms, orother signals. In other embodiments such devices can also be used asplatforms for electrical stimulus, transducers and pacer elements.

In some embodiments one or more devices described herein can be attachedto, wrapped around, wedged within, or anchored in proximity with organs,tissues or other structures such as the bladder, bowel, abdominalcavity, aorta, spine, or an incision site.

Other Methods and Devices

In one embodiment, a constant pressure device as described herein suchas a cuff can apply force to structures of the body but be forcelimiting and self adjusting, e.g. never enough force to cut off bloodsupply. These and other devices can be made to slowly inflate or slowlydeflate, or with limited PFC, self-inflate and then self-deflateaccording to different methods. Other devices according to additionalaspects can preferably dissolve after it deflates and may be comprisedof collagen, PLGA, and/or modified starches.

One of ordinary skill in the art could use or modify the devices andmethods disclosed herein or existing devices (such as adding a tissue orbone anchor) to: push back aneurism or hernia in a controlled mannerover time; slowly make space for breast implant, maintain space within atissue, between tissues or within an organ, make or maintain space foran organ transplant or pacemaker/device; hold open/take stress off ofcartilage in knee joint; push on spine to straighten spine or replace,repair, or restore the function of a portion of a vertebral body ordisc; (as a simple bag and PFC load) to soak up air (or other gas,methane) in abdomen or head and easily removal with syringe; to pull onsutures or devices as it deflates or if a shrunk device is placedbetween two strings, it can pull very hard (like pulling back string ona bow bends the wood) to pull things together gradually or with constantreadjusting force; provide a device that grows and then deflates andpass through the stomach for weight loss or ulcer treatment; provide anexpandable member on a distal tip of a Foley catheter for anchoring thedevice within a hollow organ or tissue site, provide a doughnut shapeddevice with a non-stretching band about its periphery to slowly applyconstant pressure to pinch off appendix or tumor blood supply or gentlepressure cuff to limit blood pressure to esophagus or vasculature influid communication with an aneurism, provide a sheet-like, rod-like,plate-like, or spherical expandable implant to bluntly dissect or aligntissue, anchor or open a stent.

Intravesical Infusion Devices, Materials, and Therapeutic Agents

One or more implants described herein can further comprise or serve as aplatform for drug, diagnostic, agent, or therapeutic substance delivery.Such delivery systems can include a mechanical delivery system havingone or more syringes, pistons, nozzles, valves, reservoirs for holdingthe substance, needles, atomizers, etc. Such devices can furthercomprise a MEMs, piezo-electric, or semiconductor activated port,window, nozzle or aperture. At least a portion of the device cancomprise an eluting substrate, biodegradable port or substrate, or oneor more reservoirs within either a porous membrane or a membrane havinga valve or port. Devices may further comprise a micropump,electro-osmotic pump or an osmotic delivery system to forcefully controlthe delivery of such substances and agents.

There are a number of systems known in the art to provide continuous orsustained delivery that may be adapted to the implants described herein.For example, drug delivery may be based upon: a gradual dissolution orbiophysical degradation of a matrix that releases the drug over time, abiochemical degradation of a matrix that releases the drug over time, adiffusion controlled process, a more active system such as an osmoticpump or another type of pump, or a combination thereof. For the purposesof this disclosure “biodegradable” refers to a component which maydegrade by a biophysical degradation (such as dissolution, dissociation,melting, etc.), biochemical degradation, or a combination thereof.

In biodegradable components, the drug may be physically or chemicallytrapped in the matrix. For example, the matrix may be a solid whereinthe drug is non-covalently incorporated into the matrix. In someembodiments, the drug may be dissolved in a melt of the matrix, thematrix cooled, thus trapping the drug in the matrix. For example, thebiodegradable polymer and the drug might be melt extruded.Alternatively, the drug and the matrix may be dissolved in a solvent,and the solvent may be removed. Other methods of non-covalentlyentrapping a drug in a matrix may also be used. Alternatively, the drugmay be covalently bonded to the matrix via a cleavable linkage such asan ester bond.

In some embodiments where drug delivery is based upon biophysical orbiochemical degradation of a matrix, the implant may contain one or morecomponents which are biostable. In some embodiments, this may enable theimplant to continue to perform other non-drug delivery functions afterpart of the implant has eroded from drug delivery. For example, abiostable component may be coated with one or more layers ofbiodegradable material containing a drug. In some embodiments, thebiostable component may comprise pores or holes comprising particles ofbiodegradable material containing a drug. In some embodiments, the poresor holes may provide greater surface area to which a biodegradablematerial containing a drug may be affixed or coated, which may increaseloading of the drug and be used to modulate the delivery time. In someembodiments, a component may be composed of biodegradable material andconnected or coupled to one or more biostable components. In someembodiments, a biostable component may comprise a porous or channelednetwork, such as a molecular sieve (including a cross-linked polymer).The porous network may be coated or intercalated, impregnated, orincluded with the biodegradable material comprising a drug. Thus, as thebiodegradable material degrades, the structural integrity of thecomponent may remain intact in the form of the biostable network.

Examples of biodegradable materials may include, but are not limited to,particles having a diameter in the range of about 1 nm to about 100 μm,or about 100 nm to about 10 μm, such as microspheres, microcapsules,microspherules and other such micropackages, liposomes, nanoparticles,biodegradable controlled release polymer matrices, and the like.

Some microparticles or nanoparticles may be prepared by a self-assemblyprocess, such as by the formation of micelles, microemulsions, ornanoemulsions in an aqueous medium. These compositions may be used forsustained delivery in that form, or may be modified. In someembodiments, lipids may be used to prepare these compositions. Lipidswhich may be used to create these compositions include but are notlimited to: fatty acids such as lauric acid, palmitic acid, stearicacid, arachidic acid, behenic acid, lignoceric acid, palmitoleic acid,oleic acid, linoleic acid, arachidonic acid eicosopentaenoic acidnervonic acid, etc.; triacylglycerols; glycerophospholipids;sphingolipids such as sphingomyelins, cerebrosides, gangliosides, etc.,cholesterol; etc. In some embodiments, the lipid may have about 6-100carbon atoms, about 12-60 carbon atoms, or about 12-40 carbon atoms. Alipid may also be prepared as a film, coating, or larger solid componentas a biodegradable component.

In other embodiments, a micelle, microemulsion, or nanoemulsion systemmay be polymerized to form a biodegradable polymer, thus providingmicroparticles or nanoparticles of a biodegradable particle. In someembodiments, a biodegradable polymer may be incorporated into a micelle,microemulsion, or nanoemulsion system and crosslinked to providemicroparticles or nanoparticles of a biodegradable particle.Alternatively, a biodegradable polymer may be prepared as a film,coating, or other larger solid component. Examples of usefulbiodegradable polymers include, without limitation, such materialsderived from and/or comprising organic esters and organic ethers, whichwhen degraded result in physiologically acceptable degradation products,including the monomers. Some embodiments comprise biodegrable polymersderived from and/or including, anhydrides, amides, orthoesters and thelike, by themselves or in combination with other monomers. In someembodiments, the biodegradable polymer may be an addition orcondensation polymer. The biodegradable polymer may be cross-linked ornon-cross-linked, for example not more than lightly cross-linked, suchas less than about 5%, or less than about 1% of the polymeric materialbeing cross-linked. The biodegradable polymer may also include oxygenand/or nitrogen. Oxygen may be present as oxy, e.g. hydroxy or ether,carbonyl, e.g. non-oxo-carbonyl, such as carboxylic acid ester, and thelike. Nitrogen may be present as amide, cyano and amino. In someembodiments, the biodegradable polymer comprises at least one of aester, an ether, and an amide. The polymers set forth in Heller,Biodegradable Polymers in Controlled Drug Delivery, In: CRC CriticalReviews in Therapeutic Drug Carrier Systems, Vol. 1, CRC Press, BocaRaton, Fla. 1987, pp 39-90, which describes encapsulation for controlleddrug delivery, may find use in the present devices.

In some embodiments, the biodegradable polymer may be selected from:polylactides, polyglycolides, polycaprolactones, polyanhydrides,polyamides, polyurethanes, polyesteramides, polyorthoesters, poly(aminoacids), pseudo poly(amino acids), polydioxanones, polyacetals,polyketals, polycarbonates, polyorthoesters, polyphosphazenes,polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,polyalkylene succinates, poly(malic acid), poly(amino acids),poly(methyl vinyl ether), poly(maleic anhydride), collagen, hyaluronicacid, chitin, chitosan, poly (iminocarbonates), polyoxaesters includingpolyoxaesters containing amido groups, polyamidoesters, and copolymers,terpolymers, derivatives thereof and mixtures thereof. Some embodimentsmay comprise poly lactic acid, poly glycolic acid, poly lacticacid/glycolic acid (PLGA), derivatives thereof, and mixtures thereof.Some embodiments, may comprise polymers of hydroxyaliphatic carboxylicacids, either homopolymers or copolymers, and polysaccharides.Polyesters of interest include polymers of D-lactic acid, L-lactic acid,racemic lactic acid, glycolic acid, polycaprolactone, hydroxybutyrate,hydroxyvalerate, para-dioxanone, trimethylene carbonate (and its alkylderivatives), and combinations thereof. Generally, by employing theL-lactate or D-lactate, a slowly eroding polymer or polymeric materialmay be achieved. In some embodiments, erosion may be substantiallyenhanced with the lactate racemate. Some embodiments may comprisepolysaccharides such as, without limitation, calcium alginate, andfunctionalized celluloses, particularly carboxymethylcellulose esterscharacterized by being water insoluble, a molecular weight of about 5 kDto 500 kD, for example. Some embodiments may comprise polyesters,polyethers and combinations thereof which are biocompatible and may bebiodegradable and/or bioerodible.

Continuous or sustained delivery may also be based upon a diffusioncontrolled process. In some embodiments, a component of the device maycomprise barriers to diffusion such as a selective membrane, or a solidcomponent with pores which present bottleneck to a diffusion process.For example, pores having diameters in the range of about 0.1 nm toabout 1000 nm, about 0.5 nm to about 50 nm, or about 1 nm to about 10nm, may reduce the diffusion rates of drugs and/or water, thus providingmore sustained delivery. In some materials, these barriers may comprisea molecular sieve material such as a crosslinked polymer. In someembodiments, these barriers may comprise a biostable crosslinkedpolymer.

Hydrogels may be part of a diffusion controlled or a biodegradablecomponent of a drug delivery system. In some embodiments, hydrogels arepolymers may that absorb and swell in an aqueous environment.Water-swellable hydrophilic polymers, both ionic and nonionic, oftenreferred to as “osmopolymers” and “hydrogels.” Exemplary materialsinclude polymers such as vinyl polymers, acrylics, polysaccharides,polyalkylene oxides, polyvinylpyrrolidone, polyurethanes, sodiumcroscarmellose, carrageenan, HEC, HPC, HPMC, CMC and CEC, sodiumalginate, polycarbophil, gelatin, xanthan gum, and sodium starchglycolate, and mixtures and copolymers thereof. Other materials includehydrogels comprising interpenetrating networks of polymers which may beformed by addition or by condensation polymerization, the components ofwhich may comprise hydrophilic and hydrophobic monomers such as thosejust mentioned.

An active system may comprise a pump such as an osmotic pump. An osmoticpump provides sustained or controlled delivery of a drug by osmoticpressure. These devices are described in publications such as Theeuwes,J. Pharm. ScL, 64(12):1987-91 (1975). Other active systems are alsoknown in the art.

Any drug or therapeutically active agent may be used with the devicesdisclosed herein. Suitable therapeutically active agents or drugs mayinclude, but are not limited to: antineoplastic agents, such as platinumcompounds (e.g., spiroplatin, cisplatin, and carboplatin), methotrexate,adriamycin, mitomycin, ansamitocin, bleomycin, cytosine arabinoside,arabinosyl adenine, mercaptopolylysine, vincristine, neurotoxins such asbotulinum toxin, including botulinum toxin A, busulfan, chlorambucil,melphalan (e.g., PAM, L-PAM or phenylalanine mustard), mercaptopurine,mitotane, procarbazine hydrochloride dactinomycin (actinomycin D),daunorubicin hydrochloride, doxorubicin hydrochloride, taxol, mitomycin,plicamycin (mithramycin), aminoglutethimide, estramustine phosphatesodium, flutamide, leuprolide acetate, megestrol acetate, tamoxifencitrate, testolactone, trilostane, amsacrine (m-AMSA), asparaginase(L-asparaginase) Erwina asparaginase, etoposide (VP-16), interferonα-2a, interferon α-2b, teniposide (VM-26), vinblastine sulfate (VLB),vincristine sulfate, bleomycin, bleomycin sulfate, methotrexate,adriamycin, and arabinosyl; blood products such as parenteral iron,hemin, hematoporphyrins and their derivatives; biological responsemodifiers such as muramyldipeptide, muramyltripeptide, microbial cellwall components, lymphokines (e.g., bacterial endotoxin such aslipopolysaccharide, macrophage activation factor), sub-units of bacteria(such as Mycobacteria, Corynebacteria), the synthetic dipeptideN-acetyl-muramyl-L-alanyl-D-isoglutamine; anti-fungal agents such asketoconazole, nystatin, griseofulvin, flucytosine (5-fc), miconazole,amphotericin B, ricin, and β-lactam antibiotics (e.g., sulfazecin);hormones such as growth hormone, melanocyte stimulating hormone,estradiol, beclomethasone dipropionate, betamethasone, betamethasoneacetate and betamethasone sodium phosphate, vetamethasone disodiumphosphate, vetamethasone sodium phosphate, cortisone acetate,dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate,flunisolide, hydrocortisone, hydrocortisone acetate, hydrocortisonecypionate, hydrocortisone sodium phosphate, hydrocortisone sodiumsuccinate, methylprednisolone, methylprednisolone acetate,methylprednisolone sodium succinate, paramethasone acetate,prednisolone, prednisolone acetate, prednisolone sodium phosphate,prednisolone tebutate, prednisone, triamcinolone, triamcinoloneacetonide, triamcinolone diacetate, triamcinolone hexacetonide andfludrocortisone acetate; vitamins such as cyanocobalamin neinoic acid,retinoids and derivatives such as retinol palmitate, and α-tocopherol;peptides, such as manganese super oxide dismutase; enzymes such asalkaline phosphatase; anti-allergic agents such as amelexanox;anti-coagulation agents such as phenprocoumon and heparin; circulatorydrugs such as propranolol; metabolic potentiators such as glutathione;antituberculars such as para-aminosalicylic acid, isoniazid, capreomycinsulfate cycloserine, ethambutol hydrochloride ethionamide, pyrazinamide,rifampin, and streptomycin sulfate; antivirals such as acyclovir,amantadine azidothymidine (AZT or Zidovudine), ribavirin and vidarabinemonohydrate (adenine arabinoside, ara-A); antianginals such asdiltiazem, nifedipine, verapamil, erythritol tetranitrate, isosorbidedinitrate, nitroglycerin (glyceryl trinitrate) and pentaerythritoltetranitrate; anticoagulants such as phenprocoumon, heparin; antibioticssuch as dapsone, chloramphenicol, neomycin, cefaclor, cefadroxil,cephalexin, cephradine erythromycin, clindamycin, lincomycin,amoxicillin, ampicillin, bacampicillin, carbenicillin, dicloxacillin,cyclacillin, picloxacillin, hetacillin, methicillin, nafcillin,oxacillin, penicillin G, penicillin V, ticarcillin rifampin andtetracycline; antiinflammatories such as diflunisal, ibuprofen,indomethacin, meclofenamate, mefenamic acid, naproxen, oxyphenbutazone,phenylbutazone, piroxicam, sulindac, tolmetin, aspirin and salicylates;antiprotozoans such as chloroquine, hydroxychloroquine, metronidazole,quinine and meglumine antimonate; antirheumatics such as penicillamine;narcotics such as paregoric; opiates such as codeine, heroin, methadone,morphine and opium; cardiac glycosides such as deslanoside, digitoxin,digoxin, digitalin and digitalis; neuromuscular blockers such asatracurium mesylate, gallamine triethiodide, hexafluorenium bromide,metocurine iodide, pancuronium bromide, succinylcholine chloride(suxamethonium chloride), tubocurarine chloride and vecuronium bromide;sedatives (hypnotics) such as amobarbital, amobarbital sodium,aprobarbital, butabarbital sodium, chloral hydrate, ethchlorvynol,ethinamate, flurazepam hydrochloride, glutethimide, methotrimeprazinehydrochloride, methyprylon, midazolam hydrochloride, paraldehyde,pentobarbital, pentobarbital sodium, phenobarbital sodium, secobarbitalsodium, talbutal, temazepam and triazolam; local anesthetics such asbupivacaine hydrochloride, chloroprocaine hydrochloride, etidocainehydrochloride, lidocaine hydrochloride, mepivacaine hydrochloride,procaine hydrochloride and tetracaine hydrochloride; general anestheticssuch as droperidol, etomidate, fentanyl citrate with droperidol,ketamine hydrochloride, methohexital sodium and thiopental sodium; andradioactive particles or ions such as strontium, iodide rhenium andyttrium.

In some embodiments, implants 66 provided herein may comprise aninfusion device 176 comprised of a reservoir 178 containing a drug 180and a flow-restricted exit port 182 in fluid communication with the drugin the reservoir. FIG. 51A shows a cross-section of a spherical implant66 filled with at least partially with drug 180. The flow-restrictedexit port may provide delivery of a drug over a period of at least 24hours, 5 days, 15 days or more. The device may be configured to deliverthe drug at an appropriate rate as desired by the physician. Forexample, the drug may be in a liquid form and the device may deliver thedrug at a rate of less than about 400 μl/hour or about 400 mg/hour, orin a range of about 1-100 μl/hour or about 1-100 mg/hour.

In another embodiment, an implantable infusion device 176 comprises anelongated elastomeric portion having a first end and a second end and isadapted to contain and pressurize a liquid 184, as is shown in FIG. 51B.The device may also comprise a flow controller providing an exit port182 in fluid communication with the liquid 184 in the elastomericportion. The flow controller may provide for controlled release of theliquid from the implant.

Drugs or other substances for use in the body and especially the bladdercan be provided in a variety of forms, including liquids, solids, andhydratable powders. These drugs and other materials can be used for avariety of purposes, including the treatment of urinary incontinence,urinary tract cancer, urinary tract infections, inflammatory conditionsof the urinary tract, interstitial cystitis, overactive bladdersyndrome, and to provide pain relief. In addition, the substancereleased from the device may used for diagnostic purposes.

Urinary incontinence, including urge incontinence and neurogenicincontinence, can be treated using an implant as described herein.Preferably, anticholinergic and/or antispasmodic agents are used. Inaddition, antimuscarinic agents, β-2 agonists, norepinephrine uptakeinhibitors, serotonin uptake inhibitors, calcium channel blockers,potassium channel openers, and muscle relaxants can also be used.

Urinary tract cancer, such as bladder cancer and prostate cancer, may betreated using a device by infusing antiproliferative agents, cytotoxicagents and/or chemotherapeutics. Treatment of urinary tract cancer canbe effected in conjunction with other conventional cancer treatmenttechniques, including surgical excision, and radiation therapy.

In a similar manner, infections involving the bladder, the prostate, andthe urethra, can be treated using an implant as described herein.Antibiotics, antibacterial, antifungal, anti-protozoal, antiviral andother anti-infective agents can be administered for treatment of suchinfections.

Inflammatory conditions such as interstitial cystitis, prostatitis, andurethritis can also be treated using an implant as described herein.Drugs having an anti-inflammatory and/or coating effect are useful inthis regard. Suitable drugs include dimethyl sulfoxide (DMSO), heparin,pentosanpolysulfate sodium, and flavoxate.

Implants as described herein can also be used to provide pain relief tothe patient. In this regard, a variety of anesthetic and/or analgesicagents can be infused through the implant.

An implant as described herein can also be used to administer drugs andother materials for a variety of other purposes. For example, the devicecan be used to administer glycine for purposes such as bladderirrigation.

Various treatment methods can provide for slow, continuous, intermittentor periodic release of a desired quantity of drug over a desired periodof time. In one preferred embodiment, the volume of the infuser is suchthat it can deliver the desired dose of drug over an extended period oftime, e.g., 24 hours, 5 days, 10 days, 15 days or even 20, 25, 30, 60,90 days or more. The rate of delivery in order to accomplish this resultis relatively slow. Thus, drug delivery rates within the range of0.0001, 0.001, 0.01, 0.1, 1, 5, 10, 25, 50, 75, 100, 150, or 200 μl/hr,or 0.0001, 0.001, 0.01, 0.1, 1, 5, 10, 25, 50, 75, 100, 150, or 200mg/hr can be used. Of course, slower or faster delivery rates can beselected depending upon the drug being delivered and the disease beingtreated. In any particular situation, and for any particular diseasestate, the concentration of the drug and the rate of delivery can beselected by the physician based on conventional methodologies. The rateof delivery can also be in bolus form, utilizing a programmedcontroller.

In one aspect shown in FIG. 51C, an implant has a body which comprisesat least one hollow elastomeric tube having an outer surface, an innersurface, and at least one reservoir 178 defined within the hollow tube;a drug formulation (which includes a drug) 180 contained in thereservoir 178; and one or more apertures 182 providing a passageway torelease the drug 180 from the drug delivery device. The apertures 182may be through the sidewall of the tube or through an end of the tube.The diameter of each aperture preferably is between about 20 μm andabout 300 μm. The hollow tube may be formed of a water permeablematerial. The device is configured to permit its insertion into a bodycavity and its retention in the body cavity during release of the drug.

In some embodiments, an implant can comprise a drug or a therapeuticagent. The implant can operate to intravesically deliver the drug ortherapeutic agent. The drug or therapeutic agent can be contained withinan enclosure, similar to those described above, for example.Alternatively, the drug or therapeutic agent can be contained within oneor more separate reservoirs. The reservoirs can have a flow restrictiveelement. A chamber holding a high vapor pressure media can be inpressure communication with said one or more reservoirs and can drivethe delivery of the drug or therapeutic agent out of said flowrestrictive element over time. In some embodiments, the high vaporpressure media in the chamber maintains a constant pressure within theone or more separate reservoirs operable to drive said drug ortherapeutic agent out of said one or more separate reservoirs at aselected rate.

An implant can have a degradable membrane. The degradable membrane maybe formed of biodegradable polymer material, and may have a thicknessbetween about 145 μm and about 160 μm.

In one embodiment, the drug formulation is in a solid or semi-solidform. In one embodiment adapted for use in the bladder, the drugformulation and dose are effective for treating overactive bladdersyndrome, bladder cancer, or interstitial cystitis. The drug formulationmay include an anesthetic, an analgesic, an antibiotic, or a combinationthereof. The drug formulation may further include one or morepharmaceutically acceptable excipients. In another aspect, a method isprovided for administering a drug to a patient.

Implants can be tailored to release one or more drugs in a preprogrammedmanner, for therapies requiring bolus (one-time), pulsatile, or constantdrug delivery. An implant can be implanted once and release severaldoses of drug over an extended period, without requiring surgery orfrequent interventions (such as to re-fill the drug reservoir of aconventional device).

In a preferred embodiment, an implant operates essentially as an osmoticpump. Following implantation, water permeates through the tube body,enters the reservoir, and is imbibed by the drug formulation.Solubilized drug is dispensed at a controlled rate out of the implantthrough one or more apertures, driven by osmotic pressure in thereservoir. PFC can also be used to pressurize the reservoir. Thedelivery rate can be predicted from the physicochemical parametersdefining the particular drug delivery system, according to well knownprinciples, which are described for example in Theeuwes, J. Pharm. ScL,64(12):1987-91 (1975). In this embodiment, the water can enter thereservoir in one way, mix with the drug and then exit out another waywhich has a different aperture size from the entrance. In an alternativeembodiment, the implant operates essentially by diffusion of the drugthrough one or more apertures.

In one embodiment of non-resorbable implant, the tube of the body isformed of a medical grade silicone tubing, as known in the art. Otherexamples of suitable non-resorbable materials include synthetic polymersselected from poly(ethers), poly(acrylates), poly(methacrylates),poly(vinyl pyrolidones), poly(vinyl acetates), poly(urethanes),celluloses, cellulose acetates, poly(siloxanes), poly(ethylene),poly(tetrafluoroethylene) and other fluorinated polymers,poly(siloxanes), copolymers thereof, and combinations thereof. Inanother embodiment, the device body is resorbable. In one embodiment ofresorbable device, the tube of the body is formed of a biodegradable orbioerodible polymer. Examples of suitable resorbable materials includesynthetic polymers selected from poly(amides), poly(esters),poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudo poly(aminoacids), copolymers thereof, and mixtures thereof. In a preferredembodiment, the resorbable synthetic polymers are selected frompoly(lactic acids), poly(glycolic acids), poly(lactic-co-glycolicacids), poly(caprolactones), and mixtures thereof. The size of aurological device, or other implant device, is important. The smallerthe device, the less pain and discomfort the patient will experienceduring insertion and use of the device, and particularly duringcystoscopic implantation of the device. In a preferred embodiment, thedevice body has a length of about 1 cm to about 10 cm, and when in itsshape for insertion it has an effective outer diameter (or largestcross-sectional dimension) of about 0.05 cm to 0.07 cm. (A 10 cm lengthdevice forms a ring with a diameter of 3.18 cm.) In one embodiment, theinner surface of the tube has a diameter between about 300 μm and about500 μm, and the outer surface of the tube has an diameter between about600 μm and about 900 μm.

The size of the apertures of an infusion device may be important inproviding a controlled rate of release of the drug. Where the deviceoperates as an osmotic pump, it should be small enough to minimize thecontribution to the delivery rate made by diffusion of the drug throughthe aperture, yet the aperture should be large enough to minimizehydrostatic pressure within the reservoir, which pressure undesirablywould tend to decrease the osmotic flux and/or cause the reservoirvolume to increase. Within these constraints on aperture size, one maythen vary the number of such sized apertures employed in a single device(or in a single reservoir) in order to provide a needed total rate ofdrug released. In exemplary embodiments, the diameter of the aperture isbetween about 20 μm and about 300 μm (e.g., 20 to 100 μm, 25 to 75 μm,etc.). Where the device operates primarily by a diffusion mechanism,apertures may be in this range or larger.

A single device may have apertures of two or more different sizes. Theaperture typically is circular in shape, although other shapes arepossible and envisioned, and will typically depend on manufacturingconsiderations.

The apertures can optionally have a degradable membrane disposed over orin each of the apertures, to control the time at which release of thedrug formulation begins. In one embodiment, the degradable membrane isin the form of a uniform coating covering the outer surface of the tubeof the device body. In another embodiment, the discrete degradablemembranes are provided substantially within the aperture. Combinationsof two or more degradable membranes may be used to control release fromone aperture.

The thickness of the degradable membrane in a particular system willdepend for example on the chemistry and mechanical properties of thematerial of construction selected for the degradable membrane (whichprimarily govern the rate of degradation), as well as on the desiredtime of delay of drug release for the particular drug delivery device.See, e.g., Richards Grayson, et al., “Molecular release from a polymericmicroreservoir device: Influence of chemistry, polymer swelling, andloading on device performance” Wiley InterScience (6 Apr. 2004);Richards Grayson, et al., “Multi-pulse drug delivery form a resorbablepolymeric microchip device” Nature Materials, Advance Online Publication(19 Oct. 2003); U.S. Pat. No. 6,808,522. In one embodiment, thedegradable membrane has a thickness between about 100 μm and about 200μm, such as between 145 μm and 160 μm.

Membranes can be formed of a biocompatible material. In one embodiment,the membranes are formed of a resorbable synthetic polymer such aspolyester, a poly(anhydride), or a polycaprolactone. In anotherembodiment, the membranes are formed of a resorbable biologicalmaterials such as cholesterol, other lipids and fats.

For embodiments of these devices in which it is desired to release drugover a short period of time, the degradable membrane may be fabricatedfrom quickly disintegrating materials including, for example,poly(lactide-co-glycolide) copolymers containing a high glycolidecontent, copolymers of poly(lactones) with fast degradation times,certain poly (anhydrides), hydrogels, oligosaccharides, andpolysaccharides. For applications in which a longer or delayed releasetime is desirable, the degradable membrane may be fabricated frommaterials that take longer to disintegrate, for example, a resorbablebiological materials such as cholesterol, other lipids and fats, andlipid bilayers, polymers such as poly(caprolactone) or certainpoly(anhydrides), and PLGA copolymers with high lactic acid content.

In one embodiment, an intravesical drug delivery device is used to treatinflammatory conditions such as interstitial cystitis, prostatitis, andurethritis. Representative examples of specific drugs for theseconditions include lidocaine hydrochloride, glycosaminoglycans (e.g.,chondroitin sulfate, sulodexide), pentosanpolysulfate, dimethylsulfoxide (DMSO), oxybutynin, mitomycin C, heparin, flavoxate, or acombination thereof.

In another embodiment, an intravesical drug delivery device is used toprovide pain relief to the patient. A variety of anesthetic agent,analgesic agents, and combinations thereof may be used.

An intravesical drug delivery device can be used to treat urinaryincontinence, including urge incontinence and neurogenic incontinence.Drugs that may be used include anticholinergic agents, antispasmodicagents, anti-muscarinic agents, β-2 agonists, norepinephrine uptakeinhibitors, serotonin uptake inhibitors, calcium channel blockers,potassium channel openers, and muscle relaxants.

In another embodiment, an intravesical drug delivery device is used totreat urinary tract cancer, such as bladder cancer and prostate cancer.Drugs that may be used include antiproliferative agents, cytotoxicagents, chemotherapeutic agents, or a combination thereof. The drugtreatment may be coupled with a conventional radiation or surgicaltherapy targeted to the cancerous tissue.

In still another embodiment, an intravesical drug delivery device isused to treat infections involving the bladder, the prostate, and theurethra. Antibiotics, antibacterial, antifungal, antiprotozoal,antiviral and other antiinfective agents can be administered fortreatment of such infections.

Other drugs and excipient may be used for other therapies and at othernonbladder body cavity sites. Combinations of two or more drugs, storedin (and released from) the same or separate reservoirs in the device areenvisioned. The excipient of the drug formulation may be a matrixmaterial, selected to modulate or control the rate of release of thedrug from the reservoir. In one embodiment, the matrix material may be aresorbable or non-resorbable polymer as described above. In anotherembodiment, the excipient comprises a hydrophobic or amphiphiliccompound, such as a lipid,

The drug formulation may provide a temporally modulated release profileor a more continuous or consistent release profile. Pulsatile releasecan be achieved from a plurality of reservoirs. For example, differentdegradable membrane can be used to by temporally stagger the releasefrom each of several reservoirs.

Intravesical drug delivery devices and treatment methods describedherein can provide extended, continuous, intermittent, or periodicrelease of a desired quantity of drug over a desired (predetermined)period of time. In one embodiment, the device can deliver the desireddose of drug over an extended period of time, e.g., 24 hours, 5 days, 7days, 10 days, 14 days, or 20, 25, 30, 45, 60, or 90 days, or more. Therate of delivery and dosage of the drug can be selected depending uponthe drug being delivered and the disease/condition being treated. Theuse of different degradation rates and/or excipient materials, alongwith varying the number and size of apertures in the device, can be usedto tailor the device to have different release kinetics.

In one embodiment, a porous reticulated polymeric matrix is used tofabricate the implant to provide adequate fluid permeability. Theaverage diameter or other largest transverse dimension of pores is fromabout 300 to about 10 pores per linear inch, preferably from about 300to about 25 pores per linear inch, more preferably from about 150 toabout 35 pores per linear inch, and most preferably between about 80 and40 pores per linear inch.

Various reticulated hydrophobic polyurethane foams are suitable for thispurpose. In one embodiment, structural materials for the porouselastomers are synthetic polymers, especially, but not exclusively,elastomeric polymers that are resistant to biological degradation, forexample, polycarbonate polyurethanes, polyether polyurethanes,polysiloxanes, and the like. Such elastomers are generally hydrophobicbut, may be treated to have surfaces that are less hydrophobic orsomewhat hydrophilic. In another embodiment, such elastomers may beproduced with surfaces that are less hydrophobic or somewhathydrophilic.

A porous biodurable reticulatable elastomeric partially hydrophobicpolymeric scaffold material can be provided for fabricating an implantor a material. More particularly, one embodiment provides a biodurableelastomeric polyurethane matrix which comprises a polycarbonate polyolcomponent and an isocyanate component by polymerization, crosslinkingand foaming, thereby forming pores, followed by reticulation of the foamto provide a biodurable reticulatable elastomeric product. The productis designated as a polycarbonate polyurethane, being a polymercomprising urethane groups formed from, e.g., the hydroxyl groups of thepolycarbonate polyol component and the isocyanate groups of theisocyanate component.

Of particular interest are thermoplastic elastomers such aspolyurethanes whose chemistry is associated with good biodurabilityproperties, for example. In one embodiment, such thermoplasticpolyurethane elastomers include polycarbonate polyurethanes, polyesterpolyurethanes, polyether polyurethanes, polysiloxane polyurethanes,polyurethanes with so-called “mixed” soft segments, and mixturesthereof. Mixed soft segment polyurethanes are known to those skilled inthe art and include, e.g., polycarbonate-polyester polyurethanes,polycarbonate-polyether polyurethanes, polycarbonate-polysiloxanepolyurethanes, polyester-polyether polyurethanes, polyester-polysiloxanepolyurethanes and polyether-polysiloxane polyurethanes. In anotherembodiment, the thermoplastic polyurethane elastomer comprises at leastone diisocyanate in the isocyanate component, at least one chainextender and at least one diol, and may be formed from any combinationof the diisocyanates, difunctional chain extenders and diols describedin detail above.

Some suitable thermoplastic polyurethanes for certain embodimentsinclude, but are not limited to, polyurethanes with mixed soft segmentscomprising polysiloxane together with a polyether and/or a polycarbonatecomponent, as disclosed by Meijs et al. in U.S. Pat. No. 6,313,254; andthose polyurethanes disclosed by DiDomenico et al. in U.S. Pat. Nos.6,149,678; 6,111,052; and 5,986,034, all of which are incorporatedherein by reference.

Some suitable commercially-available thermoplastic elastomers includethe line of polycarbonate polyurethanes supplied under the trademarkBIONATES by The Polymer Technology Group Inc. (Berkeley, Calif.). Forexample, the very well-characterized grades of polycarbonatepolyurethane polymer BIONATEV 80A, 55 and 90 are soluble in THF,processable, reportedly have good mechanical properties, lackcytotoxicity, lack mutagenicity, lack carcinogenicity and arenon-hemolytic. Another suitable commercially-available elastomer is theCHRONOFLEX (g) C line of biodurable medical grade polycarbonate aromaticpolyurethane thermoplastic elastomers available from CardioTechInternational, Inc. (Woburn, Mass.). Yet another suitablecommercially-available elastomer is the PELLETHANE line of thermoplasticpolyurethane elastomers, in particular the 2363 series products and moreparticularly those products designated 81A and 85A, supplied by The DowChemical Company (Midland, Mich.). These commercial polyurethanepolymers are linear, not crosslinked, polymers, therefore, they aresoluble, readily analyzable and readily characterizable.

To facilitate immobilization of the drug on the scaffold, the scaffoldmay be hydrophilized or coated with a hydrophilic coating to facilitateattachment of therapeutic agent or therapeutic agent drug bearingstructures such as biologically erodible microspheres, microcapsules orother micropackages. Hydrophilization may comprise treatment of thehydrophobic material to render the surfaces partially hydrophilic orapplication of an adhesive or application of a hydrophilic coating, ordeposit of a hydrophilic foam, for example, as described in Thomson,U.S. Pat. No. 6,617,014, incorporated herein by reference.

The hydrophilic foam coating can be made from polyurethanes containingappropriate and suitable isocyanate and polyols. Isocyanates suitablefor use are aromatic, such as, for example, toluene dilsocyanate (TDI)or methylene diphenyl isocyanate (MDI), or with a aliphaticduisosyanate, such as hydrogenated MDI or isopherone dilsocyanate. Oneexample of polyol is polyether polyols which are homopolymers ofethylene oxide, also known as polyethylene glycols, or copolymers ofethylene oxide and propylene oxides. Other examples of suitable polyolsare polyester polyol, poly (ether-co-ester) polyol, poly(ether-co-hydrocarbon) polyol, poly (ether-co-siloxane) polyol, poly(ester-co-siloxane) polyol, poly (ether-co-carbonate) polyol, poly(ester-co-carbonate) polyol, poly (ester-co-hydrocarbon) polyol, ormixtures thereof.

Higher concentrations may be used, up to over 50% by weight of solids.Coatings may also be formed in a similar fashion by first dissolving thepolyol, chain extender, crosslinker and catalyst in solvent and thenadding the isocyanate, followed by casting and curing. Highconcentrations are also possible with this method.

Polyurethane coatings may also be prepared from water-based systems(dispersions). Polyurethanes used are ionomers (cationic or anionic) or,less often, from poly urethanes containing hydrophilic chains. Cationicionomers are synthesized by the reaction of isocyanate-terminatedprepolymers with tertiary amines containing hydroxyl groups, followed byquaternization of the tertiary nitrogen atom with, for example, methylsulphate, alkyl chlorides, benzyl chloride, etc. This is then dispersedin water. Anionic ionomers are synthesized by the reaction ofisocyanate-terminated prepolymers with salts of carboxylic or sulfonicacids which incorporate two reactive groups, amine or hydroxyl. The acidgroups are first converted into salts to prevent their reaction withisocyanate. The resulting ionomer is also dispersible in water.

Alternatively, if anionic ionomers are prepared using carboxylic acidswith amine groups, the reaction may be carried out in water (the aminegroups will react with the isocyanate groups much faster than doeswater). Typical concentrations are in the range of 30-60% solids. In oneembodiment, the hydrophilic film or coating for the internal surfaces ofthe hydrophobic elastomeric material that is used to fabricate thehydrophobic scaffold or an implant can be made from flowable polymericmaterial such as a polymer solution, emulsion, microemulsion,suspension, dispersion, a liquid polymer, or a polymer melt. Forexample, the flowable polymeric material can comprise a solution of thepolymer in a volatile organic solvent. The coating or the film can haveadditional capacity to transport or bond to active ingredients that canthen be preferentially delivered.

In one embodiment, the polymeric material can comprise a thermoplasticelastomer and the flowable polymeric material can comprise a solution ofthat thermoplastic elastomer that can also be biodurable. In anotherembodiment, the polymeric material can comprise a solvent-solublebiodurable thermoplastic elastomer and the flowable polymeric materialcan comprise a solution of that solvent-soluble biodurable thermoplasticelastomer. The solvent can then be removed or allowed to evaporate tosolidify the polymeric material into a film or coating.

Suitable film-forming biodurable biocompatible non-biodegradablepolymers to be used for hydrophilic coating include polyamides,polyolefins (e.g., polypropylene, polyethylene), nonabsorbablepolyesters (e.g., polyethylene terephthalate), silicones, poly (meth)acrylates, polyesters, polyalkyl oxides (e.g., polyethylene oxide),polyvinyl alcohols, polyethylene glycols and polyvinyl pyrrolidone, aswell as hydrogels, such as those formed from crosslinked polyvinylpyrrolidinone and polyesters. Other polymers, of course, can also beused as the biocompatible polymer provided that they can be dissolved,cured or polymerized.

Suitable polymers and copolymers include polyolefins, polyisobutyleneand ethylene-a-olefin copolymers; acrylic polymers (includingmethacrylates) and copolymers; vinyl halide polymers and copolymers,such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methylether; polyvinylidene halides such as polyvinylidene fluoride andpolyvinylidene chloride; polyacrylonitrile; polyvinyl ketones; polyvinylaromatics such as polystyrene; polyvinyl esters such as polyvinylacetate; copolymers of vinyl monomers with each other and witha-olefins, such as etheylene-methyl methacrylate copolymers andethylene-vinyl acetate copolymers; acrylomitrile-styrene copolymers; ABSresins; polyamides, such as nylon 66 and polycaprolactam; alkyd resins;polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins;polyurethanes; rayon; rayon-triacetate; cellophane; cellulose and itsderivatives such as cellulose acetate, cellulose acetate butyrate,cellulose nitrate, cellulose propionate and cellulose ethers (e.g.,carboxymethyl cellulose and hydoxyalkyl celluloses); and mixturesthereof.

Suitable film-forming biodurable biocompatible biodegradable polymers tobe used for hydrophilic coating include bioabsorbable aliphaticpolyesters (e.g., homopolymers and copolymers of lactic acid, glycolicacid, lactide, glycolide, para-dioxanone, trimethylene carbonate,s-caprolactone and blends thereof). Further, biocompatible polymersinclude film-forming bioabsorbable polymers; these include aliphaticpolyesters, poly (amino acids), copoly (ether-esters), polyalkylenesoxalates, polyamides, poly (iminocarbonates), polyorthoesters,polyoxaesters including polyoxaesters containing amido groups,polyamidoesters, polyanhydrides, polyphosphazenes, biomolecules andblends thereof. For the purpose of this disclosure aliphatic polyestersinclude polymers and copolymers of lactide (which includes lactic acidd-, 1- and meso lactide), s-caprolactone, glycolide (including glycolicacid), hydroxybutyrate, hydroxyvalerate, para-dioxanone, trimethylenecarbonate (and its alkyl derivatives), 1, 4-dioxepan-2-one, 1,5-dioxepan-2-one, 6, 6-dimethyl-1, 4-dioxan-2-one and blends thereof.

In one embodiment, a biodurable matrix or the scaffold of the implantcan provide a vehicle for the delivery of and/or the controlled releaseof a pharmaceutically-active agent, for example, a drug or amicrospheres containing drug.

In another embodiment, the pharmaceutically-active agent is admixedwith, covalently bonded to and/or adsorbed in or on the coating ofreticulated elastomeric biodurable matrix to provide a pharmaceuticalcomposition or by incorporating the pharmaceutically-active agent intoadditional hydrophilic coatings.

In another embodiment, the coating polymer or the coating foam andpharmaceutically-active agent or microspheres containingpharmaceutically-active agent have a common solvent. This can provide acoating that is a solution. In another embodiment, thepharmaceutically-active agent can be present as a solid dispersion in asolution of the coating polymer in a solvent. Alternatively, apharmaceutically-active agent can be coated onto the foam, in oneembodiment, using a pharmaceutically-acceptable carrier. If melt-coatingis employed, then, in another embodiment, the pharmaceutically-activeagent withstands melt processing temperatures without substantialdiminution of its efficacy.

In another embodiment, a top coating can be applied to delay release ofthe pharmaceutically-active agent or microspheres containingpharmaceutically-active agent. In another embodiment, a top coating canbe used as the matrix for the delivery of a secondpharmaceutically-active agent. A layered coating, comprising respectivelayers of fast- and slow-hydrolyzing polymer, can be used to stagerelease of the pharmaceutically-active agent or to control release ofdifferent pharmaceutically-active agents placed in the different layers.Polymer blends may also be used to control the release rate of differentpharmaceutically-active agents or to provide a desirable balance ofcoating characteristics (e.g., elasticity, toughness) and drug deliverycharacteristics (e.g., release profile). Polymers with differing solventsolubilities can be used to build-up different polymer layers that maybe used to deliver different pharmaceutically-active agents or tocontrol the release profile of a pharmaceutically-active agents.

A reticulated elastomeric biodurable matrix or the scaffold of theimplant comprising a pharmaceutically-active agent may be formulated bymixing one or more pharmaceutically-active agent with the polymer usedto make the scaffold, with the solvent or with the polymer-solventmixture and foamed. In another embodiment, the components, polymersand/or blends used to form the foam comprise a pharmaceutically-activeagent. To form these foams, the previously described components,polymers and/or blends are admixed with the pharmaceutically-activeagent prior to forming the foam or the pharmaceutically-active agent isloaded into the foam after it is formed.

A preferred drug delivery implant material is a resiliently compressiblecomposite polyurethane foam comprising a hydrophilic polymer foam coatedon and throughout the pore surfaces of a nonabsorbable hydrophobic foamscaffold. One suitable such material is a composite polyurethane foamproduct as disclosed in Thomson, U.S. Pat. No. 6,617,014, incorporatedherein by reference, which is both compressible and water absorbent orliquid absorbent. The hydrophobic foam provides tensile strength,support and resilient compressibility enabling the desired collapsing ofthe drug delivery implant for delivery and reconstitution in situ. Thehydrophilic foam coated on the interior pore surfaces of the hydrophobicfoam can support useful quantities of a drug for release in situ. Aparticular material of this nature is identified by the trademarkCO-FOAMJ (Hydrophilix, LLC, Portland, Me. (USA)) and is referencedherein as the “CO-FOAMJ composite” or the “CO-FOAMJ foam composite”.

Useful, flexible, at least partially hydrophobic polyurethane foams andhydrophilic polymeric coatings would be known to those skilled in theart. Representative and preferred embodiments of such porousdrug-bearing materials and composites suitable for use as implantmaterials are set forth in U.S. provisional patent application Ser. No.60/471,518, filed May 15, 2003, and Ser. No. 60/471,520, filed May 15,2003, both of which are incorporated herein by reference in theirentirety.

Preferred composite foams have a composition that allows relatively freeflow of urine through the foam implant. Additionally the resiliency ofthe foam composite helps retain the drug delivery implant in place asbladder naturally contracts and expands.

Desired drugs may be incorporated into an implant in any suitablemanner. In a preferred embodiment an implant such as a cylinder, sphere,bullet, football, irregular shape, or another suitable shape comprises aporous or apertured structural scaffold coated with therapeuticagent-bearing material that releases one or more therapeutic agents.

The therapeutic agent or agents, or therapeutic agent-bearingstructures, may be adhered, incorporated in a hydrophilic foam or othercoating on the hydrophobic scaffold, or, possibly covalently bonded tothe hydrophobic scaffold or the coating.

More specifically, embodiments enable the delivery of therapeutic andother biologically useful molecules from micro drug delivery systemssuch as microspheres, microcapsules, microspherules and other suchmicropackages, liposomes, nanoparticles, biodegradable controlledrelease polymer matrices, and other such drug or biologic agentmicropackaging systems, as are known, or may become known, to thoseskilled in the art which are collectively referenced herein as“microspheres.” Preferred microspheres can be charged with abiologically useful agent and will biodegrade or bioerode to release theagent in a controlled manner.

The agents to be delivered may include one or more small molecules,macromolecules, liposomal encapsulations of molecules, micro-drugdelivery system encapsulation of therapeutic molecules, covalent linkingof carbohydrates and other molecules to therapeutic molecules, and genetherapy preparations. The microspheres or microcapsules may containtherapeutic agents, enzymes, or other compounds for the purpose ofdelayed, sustained, or otherwise controlled release.

There are several general types of controlled release systems that canbe employed. For example, therapeutic agent release can be diffusioncontrolled, meaning that the diffusion of the agent trapped within apolymer matrix is the rate-determining factor for the overall releaserate. Erosion based systems also exist in which a polymer degrades overtime and releases a therapeutic agent in an amount proportional to thegradual erosion. An osmotic pumping device uses osmotic pressure as thedriving force for release. A fourth system is based on the swelling of apolymeric matrix, such as a hydrogel. Hydrogels are polymers that absorband swell in an aqueous environment. The release of the agent isdependent on the volume increase of the gel upon swelling and is thendiffusion controlled.

In a preferred embodiment, microspheres are embedded within a layer ofhydrophilic polyurethane matrix or a layer or other hydrophilicdegradable and non-degradable polymer matrix or layer applied to thesurface of a reticulated polyurethane scaffold or other stable support.It is contemplated that the embedding of microspheres may be within anyhydrophilic polyurethane or other hydrophilic degradable andnon-degradable polymer, whether it is alone or applied to any stablesurface.

In one embodiment of preparing the microsphere-bearing composite foammaterial, microspheres can be mixed with the free polymer components ofthe hydrophilic polyurethane, in the prepolymer phase. In anotherembodiment, of preparing the microsphere-bearing composite foammaterial, microspheres can be mixed with the film or coating forminghydrophilic polymer during the solution preparing process. In anotherembodiment, polyurethane, solvent, and a therapeutic agent are added asa coating, and then the solvent is evaporated, leaving behind a coatingwith embedded microspheres. The resultant mixture can then be used tocoat hydrophobic scaffold, fixedly embedding microspheres within ahydrophilic layer, as it cures. By mixing micro spheres within thehydrophilic layer, a dispersion of microspheres throughout thehydrophilic layer coated on the surfaces of pores of the hydrophobicsupport can be obtained.

Beneficially, microspheres are substantially held in place withinhydrophilic polyurethane surface layer through covalent or otherchemical bonding, or mechanical restraint. Substantial amounts oftherapeutic agent may be incorporated within hydrophilic layer ascompared to merely covalently binding agent directly to carrier.

Furthermore, the inclusion of microspheres in polyurethane coatingexposes microspheres to whatever solution carrier was immersed within orexposed to. With both an aqueous solution and a lipid solution,microspheres are exposed to hydrated hydrophilic polyurethane layer ofcarrier and eluted into a liquid environment thereby allowingmicrospheres to be degraded and release agent in a controlled fashionfrom the hydrophilic polyurethane. This is in direct contrast tocovalently binding or adsorbing these drugs to the hydrophilic layer,which may result in unexpected or uncontrollable release of therapeuticagent. The reticulated array of struts of carrier allows quick and easyfluidic transmission of therapeutic agent. Such therapeutic agents mayinclude, but are not limited to, pharmaceuticals, therapeuticsubstances, vaccines, prophylactics and other substances depending onthe intended use or result.

Immobilization of microspheres in the hydrophilic layer of carrier isthus achieved without adhesive. The hydrophilic layer acts as a binderand when the layer becomes fully hydrated, it remains attached to theunderlying scaffold, it does not impede the release of drugs orcompounds from microspheres as they degrade, or utilize anothermechanism to release an agent over time, based on their own internalcharacteristics.

The composition of the hydrophilic layer is selected for itspermeability to the particular agent being dispersed. Such materials arewell-known.

Such materials are generally of a molecular structure which includesinterstices, i.e., pores or voids, large enough to quickly allowabsorption and relatively free movement of water molecules through thehydrophilic materials. In addition, the material, of which hydrophiliccoating is made, should have interstices large enough to allowtransmission of agent being dispersed, typically as a solution in anaqueous medium that has permeated contents of the bladder in thecoating, for example, the case of a medication dispersing from device 10situated in the human bladder.

Delivering agent locally generally results in a very small amount ofagent being required to treat a specific location within the tissue,which has substantial benefits, such as less side effects. Smaller dosesof agent will minimize the need to replace the device as often and willreduce the systemic effects that result from large drug doses as well asthe effects that the agents will have on normally functioning tissue.

Examples of anticholinergic agents are propantheline bromide,imipramine, mepenzolate bromide, isopropamide iodide, clidinium bromide,anisotropine methyl bromide, scopolamine hydrochloride, and theirderivatives. Examples of antimuscarinic agents include, but are notlimited to, hyoscyamine sulfate, atropine, methantheline bromide,emepronium bromide, anisotropine methyl bromide, and their derivatives.Examples of polysynaptic inhibitors include baclofen and itsderivatives.

Examples of beta-adrenergic stimulators include terbutaline and itsderivatives.

Examples of calcium antagonists include terodiline and its derivatives.Examples of musculotropic relaxants include, but are not limited to,dicyclomine hydrochloride, flavoxate hydrochloride, papaverinehydrochloride, oxybutynin chloride, and their derivatives. Examples ofan antineoplastic agents include, but are not limited to, carmustinelevamisole hydrochloride, flutamide,(w-methyl-N-[4-nitro-3-(trifluoromethyl) phenyl]), adriamycin,doxorubicin hydrochloride, idamycin, fluorouracil, cytoxan, mutamycin,mustargen and leucovorin calcium. Examples of antispasmodic agents arehexadiphane, magnesium gluconate, oktaverine, alibendon, butamiverine,hexahydroadiphene, 2-piperidinoethyl 3-methylflavone-8-carboxylate,4-methylumbelliferone 0,0-diethyl phosphorothiate. Examples of potassiumchannel openers include pinacidil and N-[(2-Nitrooxy)ethyl]-3-pyridinecarboxamide.

Additionally, a potential significant use of the therapeutic agentdelivery implant is as a delivery system for chemotherapeutic agents totreat bladder cancer.

By delivering the therapeutic agent continuously to the tumor, more ofthe tumor cells can be exposed to the therapeutic agent during theirproliferative phase when they are most sensitive to the chemotherapy.Additionally, the dose of the therapeutic agents can be kept lower thenin the usual interrupted, short-term treatment, thus minimizingirritation and discomfort to the patient. Further, the fact that oneminor procedure is needed for insertion and one for removal providesless inconvenience to the patient and better cost efficiency then withthe usual interrupted, short-term treatment.

Therapeutic agents that do not readily cross to the plasma barrieroffered by the wall of the urothelium may be employed for local usage,for example, to treat bladder-related conditions, while therapeuticagents that readily cross to the plasma barrier may be systemicallyadministered via bladder implantation of the implants.

Some therapeutic agents may have dual functionality, being locallyuseful and also being systemically absorbable.

A therapeutic agent delivery implant can be useful in the delivery ofantibiotics to the urinary tract, and especially bladder. Methods oftreating such cases can comprise implantation of a therapeutic agentdelivery implant containing an antibiotic into the bladder as aprophylactic measure to preempt possible urinary tract infection.

Other therapeutic agents that may be delivered to the bladder includeantispasmodics to treat overactive or spastic bladders withdesensitizing or antispasmodic agents. Overactive bladder and spasticbladder conditions area significant problem, and the possibility ofplacing an implant such as domical implant in the bladder that does notimpinge on the bladder neck (the dome-shaped implant) while allowing thechronic delivery of a desensitizing agent for comfort or anantispasmodic agent is another benefit. Additionally, systemicallyacting therapeutic agents may be delivered by an implant. There are manytherapeutic agents that require injection on a regular basis, forexample, growth hormone. Proteins of which growth hormones are exemplaryare fragile and cannot be taken orally due to destruction in the stomachdue to the action of stomach acid and of proteolytic enzymes.Accordingly, they are delivered by daily injection. Such dailyinjections can be entirely avoided or reduced by delivering such labiletherapeutic agents through the bladder mucus membrane employing theimplants described herein.

Other suitable material for the implant and other biologically activeagents for delivery by or impregnation of implants are listed in U.S.provisional application No. 61/200,147 filed Nov. 25, 2008, which isincorporated herein by reference.

Having thus described certain embodiments of the present invention,various alterations, modifications and improvements will be apparent tothose of ordinary skill in the art. Such alterations, variations andimprovements are intended to be within the spirit and scope of thepresent invention. Accordingly, the foregoing description is by way ofexample and is not intended to be limiting. In addition, any dimensionsthat appear in the foregoing description and/or the figures are intendedto be exemplary and should not be construed to be limiting on the scopeof the present invention described herein.

What is claimed is:
 1. A device for use in a human or animal body,comprising: a flexible housing comprising an outer wall and defining achamber therein; and at least one high vapor pressure medium having avapor pressure greater than the pressure in an anatomical structure anda low permeability rate through the outer wall of less than 1 ml/day atbody temperature.